Functionalized exendin-4 derivatives

ABSTRACT

The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.

RELATED APPLICATION

This application is a 35 U.S.C. 111(a) of EP 12306647.4, filed Dec. 21,2012, the entire content of which is incorporated by reference, herein,in its entirety.

FIELD OF THE INVENTION

The present invention relates to exendin-4 peptide analogues whichactivate the glucagon-like peptide 1 (GLP-1) and the glucose-dependentinsulinotropic polypeptide (GIP) receptor and optionally the glucagonreceptor (GCG) and their medical use, for example in the treatment ofdisorders of the metabolic syndrome, including diabetes and obesity, aswell as reduction of excess food intake.

BACKGROUND OF THE INVENTION

Exendin-4 is a 39 amino acid peptide which is produced by the salivaryglands of the Gila monster (Heloderma suspectum) (Eng J. et al., J.Biol. Chem., 267:7402-05, 1992). Exendin-4 is an activator of theglucagon-like peptide-1 (GLP-1) receptor, whereas it shows only very lowactivation of the GIP receptor and does not activate the glucagonreceptor (see Table 1).

TABLE 1 Potencies of exendin-4 at human GLP-1, GIP and Glucagonreceptors (indicated in pM) at increasing concentrations and measuringthe formed cAMP as described in Methods. SEQ ID EC50 hGLP-1 EC50 hGIPEC50 hGlucagon NO: peptide R [pM] R [pM] R [pM] 1 exendin-4 0.4 12500.0>10000000

Exendin-4 shares many of the glucoregulatory actions observed withGLP-1. Clinical and non-clinical studies have shown that exendin-4 hasseveral beneficial antidiabetic properties including a glucose dependentenhancement in insulin synthesis and secretion, glucose dependentsuppression of glucagon secretion, slowing down gastric emptying,reduction of food intake and body weight, and an increase in beta-cellmass and markers of beta cell function (Gentilella R et al., DiabetesObes Metab., 11:544-56, 2009; Norris S L et al., Diabet Med., 26:837-46,2009; Bunck M C et al., Diabetes Care., 34:2041-7, 2011).

These effects are beneficial not only for diabetics but also forpatients suffering from obesity. Patients with obesity have a higherrisk of getting diabetes, hypertension, hyperlipidemia, cardiovascularand musculoskeletal diseases.

Relative to GLP-1 and GIP, exendin-4 is more resistant to cleavage bydipeptidyl peptidase-4 (DPP4) resulting in a longer half-life andduration of action in vivo (Eng J., Diabetes, 45 (Suppl 2):152A(abstract 554), 1996; Deacon C F, Horm Metab Res, 36: 761-5, 2004).

Exendin-4 was also shown to be much more stable towards degradation byneutral endopeptidase (NEP), when compared to GLP-1, glucagon oroxyntomodulin (Druce M R et al., Endocrinology, 150(4), 1712-1721,2009).

Nevertheless, exendin-4 is chemically labile due to methionine oxidationin position 14 (Hargrove D M et al., Regul. Pept., 141: 113-9, 2007) aswell as deamidation and isomerization of asparagine in position 28 (WO2004/035623).

The amino acid sequence of exendin-4 is shown as SEQ ID NO: 1:

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH₂

The amino acid sequence of GLP-1(7-36)-amide is shown as SEQ ID NO: 2:

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂

Liraglutide is a marketed chemically modified GLP-1 analogue in which,among other modifications, a fatty acid is linked to a lysine inposition 20 leading to a prolonged duration of action (Drucker D J etal, Nature Drug Disc. Rev. 9, 267-268, 2010; Buse, J B et al., Lancet,374:39-47, 2009).

The amino acid sequence of Liraglutide is shown as SEQ ID NO: 3:

HAEGTFTSDVSSYLEGQAAK((S)-4-Carboxy-4-hexadecanoyl-amino-butyryl-)EFIAWLVRGRG-OH

GIP (glucose-dependent insulinotropic polypeptide) is a 42 amino acidpeptide that is released from intestinal K-cells following food intake.GIP and GLP-1 are the two gut enteroendocrine cell-derived hormonesaccounting for the incretin effect, which accounts for over 70% of theinsulin response to an oral glucose challenge (Baggio L L, Drucker D J.Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131-2157).

GIP's amino acid sequence is shown as SEQ ID NO: 4:

YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH

Glucagon is a 29-amino acid peptide which is released into thebloodstream when circulating glucose is low. Glucagon's amino acidsequence is shown in SEQ ID NO: 5:

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH

During hypoglycemia, when blood glucose levels drop below normal,glucagon signals the liver to break down glycogen and release glucose,causing an increase of blood glucose levels to reach a normal level.Hypoglycemia is a common side effect of insulin treated patients withhyperglycemia (elevated blood glucose levels) due to diabetes. Thus,glucagon's most predominant role in glucose regulation is to counteractinsulin action and maintain blood glucose levels.

Hoist (Hoist, J. J. Physiol. Rev. 2007, 87, 1409) and Meier (Meier, J.J. Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptoragonists, such as GLP-1, liraglutide and exendin-4, improve glycemiccontrol in patients with T2DM by reducing fasting and postprandialglucose (FPG and PPG). Peptides which bind and activate the GLP-1receptor are described in patent applications WO1998008871, WO2008081418and WO2008023050, the contents of which are herein incorporated byreference.

It has been described that dual activation of the GLP-1 and GIPreceptors, e.g. by combining the actions of GLP-1 and GIP in onepreparation, leads to a therapeutic principle with significantly betterreduction of blood glucose levels, increased insulin secretion andreduced body weight in mice with T2DM and obesity compared to themarketed GLP-1 agonist liraglutide (e.g. V A Gault et al., Clin Sci(Lond), 121, 107-117, 2011). Native GLP-1 and GIP were proven in humansfollowing co-infusion to interact in an additive manner with asignificantly increased insulinotropic effect compared to GLP-1 alone (MA Nauck et al., J. Clin. Endocrinol. Metab., 76, 912-917, 1993).

Designing hybrid molecules which combine agonism on the GLP-1 receptor,the GIP receptor and the glucagon receptor offers the therapeuticpotential to achieve significantly better reduction of blood glucoselevels, increased insulin secretion and an even more pronouncedsignificant effect on body weight reduction compared to the marketedGLP-1 agonist liraglutide (e.g. VA Gault et al., Clin Sci (Lond), 121,107-117, 2011).

Compounds of this invention are exendin-4 derivatives, which showagonistic activity at the GLP-1 and the GIP receptor and optionally theglucagon receptor and which have—among others—preferably the followingmodifications: Tyr at position 1 and Ile at position 12.

Surprisingly, it was found that the modification of the selective GLP-1Ragonist Exendin-4 by Tyr in position 1 and Ile in position 12 results ina peptide with high dual activity at the GLP-1 and GIP receptors. Thisobservation is surprising, since the same modification in other GLP-1agonists, such as GLP-1 itself, does not result in high activity at theGIP receptor, as shown in Table 2.

TABLE 2 Potencies of exendin-4 and GLP-1 peptide analogues at GLP-1 andGIP receptors (indicated in pM) at increasing concentrations andmeasuring the formed cAMP as described in Methods. SEQ ID EC50 hGIP REC50 hGLP-1 R NO: peptide [pM] [pM] 6 Tyr(1)Ile(12)-exendin-4 93.9 1.3 7Tyr(1)Ile(12)-GLP1 3660.0 5.0

Peptides which bind and activate both the GIP and the GLP-1 receptor andoptionally the glucagon receptor, and improve glycaemic control,suppress body weight gain and reduce food intake are described in patentapplications WO 2011/119657 A1, WO 2012/138941 A1, WO 2010/011439 A2, WO2010/148089 A1, WO 2011/094337 A1, WO 2012/088116 A2, the contents ofwhich are herein incorporated by reference. These applications disclosethat mixed agonists of the GLP-1 receptor, the GIP receptor andoptionally the glucagon receptor can be designed as analogues of thenative GIP or glucagon sequences.

Compounds of this invention are exendin-4 peptide analogues comprisingleucine in position 10 and glutamine in position 13. Krstenansky et al.(Biochemistry, 25, 3833-3839, 1986) show the importance of residues 10to 13 of glucagon for its receptor interactions and activation ofadenylate cyclase. In the exendin-4 peptide analogues of this invention,several of the underlying residues are different from said of glucagon.In particular, residues Tyr10 and Tyr13, are replaced by leucine inposition 10 and glutamine, a non-aromatic polar amino acid, in position13. This replacement, especially in combination with isoleucine inposition 23 and glutamate in position 24 leads to exendin-4 derivativeswith potentially improved biophysical properties as solubility oraggregation behavior in solution. The non-conservative replacement of anaromatic amino acid with a polar amino acid in position 13 of anexendin-4 analogue surprisingly leads to peptides with high activity onthe GIP receptor and optionally on the glucagon receptor.

Furthermore, compounds of this invention are exendin-4 derivatives withfatty acid acylated residues in position 14. This fatty acidfunctionalization in position 14 results in an improved pharmacokineticprofile. Surprisingly, the fatty acid functionalization in position 14also leads to peptides with a significantly higher GIPR activity, forexample those shown in Example 9, Table 8.

BRIEF SUMMARY OF THE INVENTION

Provided herein are exendin-4 analogues which potently activate theGLP-1 and the GIP receptor and optionally the glucagon receptor. Inthese exendin-4 analogues—among other substitutions—methionine atposition 14 is replaced by an amino acid carrying an —NH₂ group in theside-chain, which is further substituted with a lipophilic side-chain(e.g. a fatty acid optionally combined with a linker).

The invention provides a peptidic compound having the formula (I):R¹—Z—R²  (I)wherein Z is a peptide moiety having the formula (II)

Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-X40 (II)

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R⁵, —S(O)₂—R⁵ or R⁵, preferably        by —C(O)—R⁵, wherein R⁵ may be a moiety comprising up to 50 or        up to 100 carbon atoms and optionally heteroatoms selected from        halogen, N, O, S and/or P,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Ile, Glu, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala, Arg,        Lys, Aib, Leu and Tyr,    -   X19 represents an amino acid residue selected from Ala, Val, Gln        and Aib,    -   X20 represents an amino acid residue selected from Gln, Aib,        Phe, Leu, Lys, His, Arg, Pip, (S)MeLys, (R)MeLys, (S)MeOrn and        (R)MeOrn,    -   X21 represents an amino acid residue selected from Asp, Glu, Leu        and Tyr,    -   X28 represents an amino acid residue selected from Asn, Ala,        Arg, Lys, Aib and Ser,    -   X29 represents an amino acid residue selected from Gly, Thr,        Aib, D-Ala and Ala,    -   X40 is absent or represents an amino acid residue having a side        chain with an —NH₂ group, wherein the —NH₂ side chain group is        optionally functionalized by —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R⁵,        —S(O)₂—R⁵ or R⁵, preferably by —C(O)—R⁵, wherein R⁵ may be a        moiety comprising up to 50 or up to 100 carbon atoms and        optionally heteroatoms selected from halogen, N, O, S and/or P,    -   R¹ represents NH₂,    -   R² represents OH or NH₂    -   or a salt or solvate thereof.

The compounds of the invention are GLP-1 and GIP receptor agonists andoptionally glucagon receptor agonists as determined by the observationthat they are capable of stimulating intracellular cAMP formation. Invitro potency determination in cellular assays of agonists is quantifiedby determining the concentrations that cause 50% activation of maximalresponse (EC50) as described in Methods.

In certain embodiments, the invention therefore provides a peptidiccompound having the formula (I):R¹—Z—R²  (I)wherein Z is a peptide moiety having the formula (II)

Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-X40 (II)

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R⁵, —S(O)₂—R⁵ or R⁵, preferably        by —C(O)—R⁵, wherein R⁵ is a moiety comprising up to 50 or up to        100 carbon atoms and optionally heteroatoms selected from        halogen, N, O, S and/or P,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Ile, Glu, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala, Arg,        Lys, Aib, Leu and Tyr,    -   X19 represents an amino acid residue selected from Ala, Val, Gln        and Aib,    -   X20 represents an amino acid residue selected from Gln, Aib,        Phe, Leu, Lys, His, Arg, Pip, (S)MeLys, (R)MeLys, (S)MeOrn and        (R)MeOrn,    -   X21 represents an amino acid residue selected from Asp, Glu, Leu        and Tyr,    -   X28 represents an amino acid residue selected from Asn, Ala,        Arg, Lys, Aib and Ser,    -   X29 represents an amino acid residue selected from Gly, Thr,        Aib, D-Ala and Ala,    -   X40 is absent or represents an amino acid residue having a side        chain with an —NH₂ group, wherein the —NH₂ side chain group is        optionally functionalized by —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R⁵,        —S(O)₂—R⁵ or R⁵, preferably by —C(O)—R⁵, wherein R⁵ may be a        moiety comprising up to 50 or up to 100 carbon atoms and        optionally heteroatoms selected from halogen, N, O, S and/or P,    -   R¹ represents    -   R² represents OH or NH₂.    -   or a salt or solvate thereof, wherein the peptidic compound has        a relative activity of at least 0.04%, preferably at least        0.08%, more preferably at least 0.2% compared to that of natural        GIP at the GIP receptor.

In addition, the peptidic compound, particularly with a lysine atposition 14 which is further substituted with a lipophilic residue,exhibits a relative activity of at least 0.07%, preferably at least0.1%, more preferably at least 0.14%, more preferably at least 0.35% andeven more preferably at least 0.4% compared to that of GLP-1 (7-36) atthe GLP-1 receptor.

In addition, the peptidic compound, particularly with a lysine atposition 14 which is further substituted with a lipophilic residue,exhibits a relative activity of at least 0.04% (i.e. EC₅₀<1000 pM), morepreferably 0.08% (i.e. EC₅₀<500 pM) and even more preferably 0.2% (i.e.EC₅₀<200 pM) compared to that of natural GIP at the GIP receptor(EC₅₀=0.4 pM).

Optionally, in some embodiments, the peptidic compound, particularlywith a lysine at position 14 which is further substituted with alipophilic residue, exhibits a relative activity of at least 0.1%,preferably at least 0.2%, more preferably at least 0.3%, more preferablyat least 0.4% and even more preferably at least 0.5% compared to that ofnatural glucagon at the glucagon receptor.

The term “activity” as used herein preferably refers to the capabilityof a compound to activate the human GLP-1 receptor, the human GIPreceptor and optionally the human glucagon receptor. More preferably theterm “activity” as used herein refers to the capability of a compound tostimulate intracellular cAMP formation. The term “relative activity” asused herein is understood to refer to the capability of a compound toactivate a receptor in a certain ratio as compared to another receptoragonist or as compared to another receptor. The activation of thereceptors by the agonists (e.g. by measuring the cAMP level) isdetermined as described herein, e.g. as described in the examples.

According to one embodiment, the compounds of the invention have an EC₅₀for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less;more preferably of 150 pM or less, more preferably of 100 pM or less,more preferably of 90 pM or less, more preferably of 80 pM or less, morepreferably of 70 pM or less, more preferably of 60 pM or less, morepreferably of 50 pM or less, more preferably of 40 pM or less, morepreferably of 30 pM or less, and more preferably of 20 pM or less.

According to one embodiment, the compounds of the invention have an EC₅₀for hGIP receptor of 500 pM or less, preferably of 200 pM or less; morepreferably of 150 pM or less, more preferably of 100 pM or less, morepreferably of 90 pM or less, more preferably of 80 pM or less, morepreferably of 70 pM or less, more preferably of 60 pM or less, morepreferably of 50 pM or less, more preferably of 40 pM or less, morepreferably of 30 pM or less, and more preferably of 20 pM or less.

According to another embodiment, the compounds of the invention haveoptionally an EC₅₀ for hGlucagon receptor of 500 pM or less, preferablyof 200 pM or less; more preferably of 150 pM or less, more preferably of100 pM or less, more preferably of 90 pM or less, more preferably of 80pM or less, more preferably of 70 pM or less, more preferably of 60 pMor less, more preferably of 50 pM or less, more preferably of 40 pM orless, more preferably of 30 pM or less, and more preferably of 20 pM orless.

According to another embodiment, the compounds of the invention have anEC₅₀ for hGLP-1 receptor of 500 pM or less, preferably of 200 pM orless; more preferably of 150 pM or less, more preferably of 100 pM orless, more preferably of 90 pM or less, more preferably of 80 pM orless, more preferably of 70 pM or less, more preferably of 60 pM orless, more preferably of 50 pM or less, more preferably of 40 pM orless, more preferably of 30 pM or less, and more preferably of 20 pM orless, and/or an EC₅₀ for hGIP receptor of 500 pM or less, preferably of200 pM or less; more preferably of 150 pM or less, more preferably of100 pM or less, more preferably of 90 pM or less, more preferably of 80pM or less, more preferably of 70 pM or less, more preferably of 60 pMor less, more preferably of 50 pM or less, more preferably of 40 pM orless, more preferably of 30 pM or less, and more preferably of 20 pM orless, and/or optionally an EC₅₀ for hGlucagon receptor of 500 pM orless, preferably of 200 pM or less; more preferably of 150 pM or less,more preferably of 100 pM or less, more preferably of 90 pM or less,more preferably of 80 pM or less, more preferably of 70 pM or less, morepreferably of 60 pM or less, more preferably of 50 pM or less, morepreferably of 40 pM or less, more preferably of 30 pM or less, and morepreferably of 20 pM or less.

In still another embodiment, the EC₅₀ for both receptors, i.e. for thehGLP-1 receptor and for the hGIP receptor, is 500 pM or less, morepreferably 200 pM or less, more preferably 150 pM or less, morepreferably 100 pM or less, more preferably 90 pM or less, morepreferably 80 pM or less, more preferably 70 pM or less, more preferably60 pM or less, more preferably 50 pM or less, more preferably 40 pM orless, more preferably 30 pM or less, more preferably 20 pM or less.

In still another embodiment, the EC₅₀ for all three receptors, i.e. forthe hGLP-1 receptor, for the hGIP receptor and for the hGlucagonreceptor, is 500 pM or less, more preferably 200 pM or less, morepreferably 150 pM or less, more preferably 100 pM or less, morepreferably 90 pM or less, more preferably 80 pM or less, more preferably70 pM or less, more preferably 60 pM or less, more preferably 50 pM orless, more preferably 40 pM or less, more preferably 30 pM or less, morepreferably 20 pM or less.

The EC₅₀ for hGLP-1 receptor, hGIP receptor and hGlucagon receptor maybe determined as described in the Methods herein and as used to generatethe results described in Example 9.

The compounds of the invention have the ability to reduce the intestinalpassage, to increase the gastric content and/or to reduce the foodintake of a patient. These activities of the compounds of the inventioncan be assessed in animal models known to the skilled person and alsodescribed herein in the Methods. The results of such experiments aredescribed in Examples 11 and 12. Preferred compounds of the inventionmay increase the gastric content of mice, preferably of femaleNMRI-mice, if administered as a single dose, preferably subcutaneousdose, of 0.02 mg/kg body weight by at least 25%, more preferably by atleast 30%, more preferably by at least 40%, more preferably by at least50%, more preferably by at least 60%, more preferably by at least 70%,more preferably by at least 80%.

Preferably, this result is measured 1 h after administration of therespective compound and 30 mins after administration of a bolus, and/orreduces intestinal passage of mice, preferably of female NMRI-mice, ifadministered as a single dose, preferably subcutaneous dose, of 0.02mg/kg body weight at least by 45%; more preferably by at least 50%, morepreferably by at least 55%, more preferably by at least 60%, and morepreferably at least 65%; and/or reduces food intake of mice, preferablyof female NMRI-mice, over a period of 22 h, if administered as a singledose, preferably subcutaneous dose of 0.01 mg/kg body weight by at least10%, more preferably 15%, and more preferably 20%.

The compounds of the invention have the ability to reduce blood glucoselevel, and/or to reduce HbA1c levels of a patient. These activities ofthe compounds of the invention can be assessed in animal models known tothe skilled person and also described herein in the Methods. The resultsof such experiments are described in Examples 13, 14, 16 and 17.

Preferred compounds of the invention may reduce blood glucose level ofmice, preferably in female leptin-receptor deficient diabetic db/db miceover a period of 24 h, if administered as a single dose, preferablysubcutaneous dose, of 0.01 mg/kg body weight by at least 4 mmol/L; morepreferably by at least 6 mmol/L, more preferably by at least 8 mmol/L.If the dose is increased to 0.1 mg/kg body weight a more pronouncedreduction of blood glucose levels can be observed in mice over a periodof 24 h, if administered as a single dose, preferably subcutaneous dose.Preferably the compounds of the invention lead to a reduction by atleast 7 mmol/L; more preferably by at least 9 mmol/L, more preferably byat least 11 mmol/L. The compounds of the invention preferably reduce theincrease of HbA1c levels of mice over a period of 4 weeks, ifadministered at a daily dose of 0.01 mg/kg to about the ignition value.

The compounds of the invention also have the ability to reduce bodyweight of a patient. These activities of the compounds of the inventioncan be assessed in animal models known to the skilled person and alsodescribed herein in the Methods and in Examples 13 and 15.

Surprisingly, it was found that peptidic compounds of the formula (I),particularly those with a lysine (or close analogues) at position 14which is further substituted with a lipophilic residue, showed verypotent GLP-1 and GIP receptor activation; additionally in combinationwith amino acids like Gln in position 3 also very potent glucagonreceptor activation can be provided.

It is described in the literature (Murage E N et al., Bioorg. Med. Chem.16 (2008), 10106-10112), that a GLP-1 analogue with an acetylated Lysineat Pos. 14 showed significantly reduced potency compared to naturalGLP-1.

Furthermore, oxidation (in vitro or in vivo) of methionine, present inthe core structure of exendin-4, is not possible anymore for peptidiccompounds of the formula (I).

Further, compounds of the invention preferably have a high solubility atacidic and/or physiological pH values, e.g., at pH 4.5 and/or at pH 7.4at 25° C., in another embodiment at least 0.5 mg/ml and in a particularembodiment at least 1.0 mg/ml.

Furthermore, according to one embodiment, compounds of the inventionpreferably have a high stability when stored in solution. Preferredassay conditions for determining the stability is storage for 7 days at25° C. in solution at pH 4.5 or pH 7.4. The remaining amount of peptideis determined by chromatographic analyses as described in Methods andExamples. Preferably, after 7 days at 25° C. in solution at pH 4.5 or pH7.4, the remaining peptide amount is at least 80%, more preferably atleast 85%, even more preferably at least 90% and even more preferably atleast 95%.

Preferably, the compounds of the present invention comprise a peptidemoiety Z (formula II) which is a linear sequence of 39-40 aminocarboxylic acids, particularly α-amino carboxylic acids linked bypeptide, i.e. carboxamide, bonds.

In one embodiment position X14 represents an amino acid residue with afunctionalized —NH₂ side chain group, such as functionalized Lys, Orn,Dab, or Dap, more preferably functionalized Lys and X40 is absent orrepresents Lys.

An amino acid residue with an —NH₂ side chain group, e.g. Lys, Orn, Dabor Dap, may be functionalized in that at least one H atom of the —NH₂side chain group is replaced by —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R⁵,—S(O)₂—R⁵ or R⁵, preferably by —C(O)—R⁵, wherein R⁵ is a moietycomprising up to 50 or up to 100 carbon atoms and optionally heteroatomsselected from halogen, N, O, S and/or P.

In certain embodiments, R⁵ may comprise a lipophilic moiety, e.g. anacyclic linear or branched saturated hydrocarbon group, wherein R⁵particularly comprises an acyclic linear or branched (C₄-C₃₀) saturatedor unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturatedor aromatic group, particularly a mono-, bi-, or tricyclic groupcomprising 4 to 14 carbon atoms and 0, 1, or 2 heteroatoms selected fromN, O, and S, e.g. cyclohexyl, phenyl, biphenyl, chromanyl, phenanthrenylor naphthyl, wherein the acyclic or cyclic group may be unsubstituted orsubstituted e.g. by halogen, —OH and/or CO₂H.

More preferred groups R⁵ may comprise a lipophilic moiety, e.g. anacyclic linear or branched (C₁₂—O₂₂) saturated or unsaturatedhydrocarbon group. The lipophilic moiety may be attached to the —NH₂side chain group by a linker in all stereoisomeric forms, e.g. a linkercomprising one or more, e.g. 2, 3 or 4, amino acid linker groups such asγ-aminobutyric acid (GABA), ε-aminohexanoic acid (ε-Ahx), γ-Glu and/orβ-Ala. In one embodiment the lipophilic moiety is attached to the —NH₂side chain group by a linker. In another embodiment the lipophilicmoiety is directly attached to the —NH₂ side chain group. Specificexamples of amino acid linker groups are (β-Ala)₁₋₄, (γ-Glu)₁₋₄,(ε-Ahx)₁₋₄, or (GABA)₁₋₄. Preferred amino acid linker groups are β-Ala,γ-Glu, β-Ala-β-Ala and γ-Glu-γ-Glu.

Specific preferred examples for —C(O)—R⁵ groups are listed in thefollowing Table 3, which are selected from the group consisting of(S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-Hexadecanoylamino-butyryl-,4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-,4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-,6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-,Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-,(S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoyl-amino)-propionylamino]-propionylamino}-butyryl-,(S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-,(S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-,(S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl-,(S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl-,(S)-4-Carboxy-4-tetradecanoylamino-butyryl-,(S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl-,(S)-4-Carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-,(S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-,(S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-,(S)-4-Carboxy-4-henicosanoylamino-butyryl-,(S)-4-Carboxy-4-docosanoylamino-butyryl-,(S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-,(S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-,(S)-4-Carboxy-4-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-,(S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-,(S)-4-Carboxy-4-icosanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,3-(3-Octadecanoyl-amino-propionylamino)-propionyl-,3-(3-Hexadecanoyl-amino-propionyl-amino)-propionyl-,3-Hexadecanoylamino-propionyl-,(S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]-phenanthren-17-yl)-pentanoylamino]-butyryl-,(S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-,(S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-,Tetradecanoyl-, 11-Carboxy-undecanoyl-,11-Benzyloxycarbonyl-undecanoyl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-tetra-decanoylamino-butyrylamino)-butyryl-,6-[Hydroxy-(naphthalene-2-yloxy)-phosphoryloxy]-hexanoyl-,6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-,4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-,4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-hepta-decanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-hepta-decanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-,2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl,(S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1H-tetrazol-5-yl-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]ethoxy}-ethoxy)-acetyl-,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(11-carboxy-undecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoyl-amino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,and(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-.

Further preferred are stereoisomers, particularly enantiomers of thesegroups, either S- or R-enantiomers. The term “R” in Table 3 is intendedto mean the attachment site of —C(O)—R⁵ at the peptide back bone, i.e.particularly the ε-amino group of Lys.

TABLE 3 structure IUPAC name

(S)-4-Carboxy- 4-hexadecanoylamino- butyryl- γE-x53

(S)-4-Carboxy- 4-octadecanoylamino- butyryl- γE-x70

4-Hexadecanoylamino- butyryl- GABA- x53

4-[3-[(R)-2,5,7,8- tetramethyl-2- ((4R,8R)- 4,8,12-trimethyl-tridecyl)-chroman-6- yloxycarbonyl]- propionylamino]- butyryl GABA- x60

4-octadecanoylamino- butyryl- GABA- x70

4-((Z)-octadec-9- enoylamino)-butyryl- GABA- x74

6-[(4,4-Diphenyl- cyclohexyloxy)- hydroxy- phosphoryloxy]- hexanoyl-Phospho1

Hexadecanoyl- x53

(S)-4-Carboxy-4- (15-carboxy- pentadecanoylamino)- butyryl- x52

(S)-4-Carboxy-4-{3- [3-((2S,3R,4S,5R)-5- carboxy-2,3,4,5- tetrahydroxy-pentanoylamino)- propionylamino]- propionylamino}- butyryl γE-x59

(S)-4-Carboxy-4-{3-[(R)- 2,5,7,8-tetramethyl-2- ((4R,8R)-4,8,12-trimethyl-tridecyl)- chroman-6- yloxycarbonyl]- propionylamino}-butyryl- γE-x60

(S)-4-Carboxy-4- ((9Z,12Z)- octadeca-9,12- dienoylamino)- butylryl-γE-x61

(S)-4-Carboxy-4- [6-((2S,3R,4S,5R)-5- carboxy-2,3,4,5- tetrahydroxy-pentanoylamino)- hexanoylamino]- butyryl γE-x64

(S)-4-Carboxy-4- ((2S,3R,4S,5R)-5- carboxy-2,3,4,5- tetrahydroxy-pentanoylamino)- butyryl γE-x65

(S)-4-Carboxy-4- tetradecanoylamino- butyryl γE-x69

(S)-4-(11- Benzyloxycarbonyl- undecanoylamino)- 4-carboxy-butyryl γE-x72

(S)-4-Carboxy-4- [11-((2S,3R,4S,5R)- 2,3,4,5,6-pentahydroxy-hexylcarbamoyl) undecanoylamino]- butyryl- γE-x73

(S)-4-Carboxy-4- ((Z)-octadec-3- enoylamino)-butyryl- γE-x74

(S)-4-Carboxy-4- (4-dodecyloxy- benzoylamino)-butyryl- γE-x75

(S)-4-Carboxy-4- henicosanoylamino- butyryl- γE-x76

(S)-4-Carboxy-4- docosanoylamino- butyryl- γE-x77

(S)-4-Carboxy-4- ((Z)-nonadec-10- enoylamino)-butyryl- γE-x79

(S)-4-Carboxy-4- (4-decyloxy- benzoylamino)-butyryl- γE-x80

(S)-4-Carboxy-4- [(4′-octyloxy- biphenyl-4- carbonyl)amino]- butyryl-γE-x81

(S)-4-Carboxy-4- (12-phenyl- dodecanoylamino)- butyryl- γE-x82

(S)-4-Carboxy-4- icosanoylamino- butyryl- γE-x95

(S)-4-Carboxy-4- ((S)-4-carboxy-4- hexadecanoylamino- butyrylamino)-butyryl- γE-γE-x53

(S)-4-Carboxy-4- ((S)-4-carboxy-4- octadecanoylamino- butyrylamino)-butyryl- γE-γE-x70

3-(3- Octadecanoylamino- propionyl- amino)-propionyl- β-Ala-β-Ala- x70

3-(3- Hexadecanoylamino- propionyl- amino)-propionyl- β-Ala-β-Ala- x53

3-Hexadecanoylamino- propionyl- β-Ala-x53

(S)-4-Carboxy-4-[(R)-4- ((3R,5S,7R,8R, 9R,10S,12S,13R, 14R,17R)-3,7,12-trihydroxy- 8,10,13-trimethyl- hexadecahydro- cyclopenta[a]phenanthren-17-yl)- pentanoylamino]- butyryl- γE-x16

(S)-4-Carboxy-4-[(R)-4- ((3R,5R,8R,9S,10S,13R, 14S,17R)-3-hydroxy-10,13-dimethyl- hexadecahydro- cyclopenta[a] phenanthren-17-yl)-pentanoylamino]- butyryl- γE-x19

(S)-4-Carboxy-4- ((9S,10R)-9,10,16- trihydroxy- hexadecanoylamino)-butyryl- γE-x25

tetradecanoyl- x69

11-Carboxy-undecanoyl- x71

11-Benzyloxycarbonyl- undecanoyl x72

(S)-4-Carboxy-4-((S)-4- carboxy-4- tetradecanoylamino- butyrylamino)-butyryl- γE-γE-x69

6-[Hydroxy- (naphthalen- 2-yloxy)- phosphoryloxy]- hexanoyl- Phospho2

6-[Hydroxy-(5-phenyl- pentyloxy)- phosphoryloxy]- hexanoyl- Phospho3

4-(Naphthalene-2- sulfonylamino)- 4-oxo-butyryl- Sulfonamid 1

4-(Biphenyl-4- sulfonylamino)-4- oxo-butyryl Sulfonamid 2

(S)-4-Carboxy-4-((S)- 4-carboxy-4-[2-(2- (2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}- ethoxy)-acetylamino]-butyrylamino}-butyryl- x100

(S)-4-Carboxy-4- [2-(2-{2-[2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}- ethoxy)-acetylamino]- butyryl- x101

(S)-4-Carboxy-4-{(S)- 4-carboxy-4-[2-(2- {2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)- acetylamino]-ethoxy}- ethoxy)-acetylamino]-butyrylamino]-butyryl x102

(S)-4-Carboxy-2- [2-(2-{2-[2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}- ethoxy)-acetylamino]- butyryl x103

(S)-4-Carboxy-4-{(S)- 4-carboxy-4-[2-(2- {2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x104

(S)-4-Carboxy-4- [2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)- acetylamino]-butyryl x105

(S)-4-Carboxy-2-{(S)- 4-carboxy-2- [2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)- acetylamino]- butyrylamino}-butyryl x106

(S)-4-Carboxy-2- [2-(2-{2-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)- acetylamino]-butyryl x107

2-(2-{2-[2-(2-{2-[(S)-4- Carboxy-4-(17-carboxy- heptadecanoylamino)-butyrylamino]- ethoxy}-ethoxy)- acetylamino]- ethoxy}-ethoxy)-acetyl-x108

2-(2-{2-[(S)-4- Carboxy-4-(17-carboxy- heptadecanoylamino)-butyrylamino]- ethoxy}-ethoxy)- acetyl- x109

(S)-4-Carboxy-4-((S)-4- carboxy-4-((S)-4- carboxy-4-[(S)-4-carboxy-4-(19-carboxy- nonadecanoylamino)- butyrylamino]- butyrylamino}-butyrylamino)-butyryl x110

2-(2-{2-[2-(2-{2-[(S)-4- Carboxy-4-(16-1H- tetrazol-5-yl-hexadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)- acetylamino]-ethoxy}-ethoxy)-acetyl- x111

2-(2-{2-[2-(2-{2-[(S)-4- Carboxy-4-(16- carboxy- hexadecanoylamino)-butyrylamino]- ethoxy}-ethoxy)- acetylamino]- ethoxy}-ethoxy)-acetylx112

(S)-4-Carboxy-4- {(S)-4-carboxy-4-[(S)-4- carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]- butyrylamino)-butyryl x113

(S)-4-Carboxy-4-((S)- 4-carboxy-4-{2-[2-(2- {2-[2-(2-{(S)-4-carboxy-4-[10-(4- carboxy-phenoxy)- decanoylamino)- butyrylamino}-ethoxy)-ethoxy]- butyrylamino}- ethoxy)-ethoxy]- acetylamino}-ethoxy)-ethoxy]- acetylamino}-butyryl x114

(S)-4-Carboxy-4-((S)-4- carboxy-4-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-(7-carboxy- heptanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x115

(S)-4-Carboxy-4-{(S)-4- carboxy-4-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-(11-carboxy- undecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x116

(S)-4-Carboxy-4-{(S)-4- carboxy-4-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-(13-carboxy- tridecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x117

(S)-4-Carboxy-4-{(S)-4- carboxy-4-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-(15-carboxy- pentadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x118

(S)-4-Carboxy-4-{(S)-4- carboxy-4-[2-(2-{2-[2- (2-{2-[(S)-4-carboxy-4-(15-carboxy- nonadecanoylamino)- butyrylamino]- ethoxy}-ethoxy)-acetylamino]- ethoxy}-ethoxy)- acetylamino]- butyrylamino}- butyryl x119

In some embodiments, the invention relates to peptidic compounds ofFormula (I) as defined above, wherein X14 represents an amino acidresidue selected from Lys, Orn, Dab and Dap, wherein the —NH₂ side chaingroup is functionalized by —C(O)—R⁵, X40 represents an amino acidresidue selected from Lys, Orn, Dab and Dap, wherein the —NH₂ side chaingroup can be functionalized by —C(O)—R⁵, and R⁵ is a lipophilic moietyselected from an acyclic linear or branched (C₄-C₃₀) saturated orunsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated oraromatic group, wherein the lipophilic moiety may be attached to the—NH₂ side chain group by a linker selected from (β-Ala)₁₋₄, (γ-Glu)₁₋₄,(ε-Ahx)₁₋₄, or (GABA)₁₋₄ in all stereoisomeric forms.

In certain embodiments, X14 represents an amino acid residue with afunctionalized —NH₂ side chain group, such as functionalized Lys, Orn,Dab or Dap, wherein at least one H atom of the —NH₂ side chain group isreplaced by —C(O)—R⁵, which is selected from the group consisting of thesubstituents according to Table 3 above.

In some embodiments, X14 represents an amino acid residue selected fromLys, Orn, Dab and Dap, wherein the —NH₂ side chain group isfunctionalized by —C(O)—R⁵, X40 represents an amino acid residueselected from Lys, Orn, Dab and Dap, wherein the —NH₂ side chain groupcan be functionalized by —C(O)—R⁵, and —C(O)—R⁵ is selected from thegroup consisting of the substituents according to Table 3 above.

In some embodiments of the invention, position X14 and/or X40 in formula(II) represents Lysine (Lys). According to some embodiments, Lys atposition 14 and optionally at position 40 is functionalized, e.g. with agroup —C(O)R⁵ as described above. In other embodiments, X40 is absentand X14 is Lys functionalized with —C(O)—R⁵, —C(O)O—R⁵, —C(O)NH—R5,—S(O)2-R⁵ or R⁵, preferably by —C(O)—R⁵, wherein R⁵ is as defined above.In particular, X14 is Lys functionalized with C(O)—R⁵, which is selectedfrom the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl(γE-x53), (S)-4-carboxy-4-octadecanoylamino-butyryl (γE-x70),4-hexadecanoylamino-butyryl (GABA-x53),4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-(GABA-x60),4-octadecanoylamino-butyryl (GABA-x70),4-((Z)-octadec-9-enoylamino)-butyryl (GABA-x74),6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl(Phospho1), Hexadecanoyl (x53),(S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl (x52),(S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl(γE-x59),(S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl(γE-x60), (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl(γE-x61),(S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl(γE-x64),(S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl(γE-x65), (S)-4-carboxy-4-tetradecanoylamino-butyryl (γE-x69),(S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl (γE-x72),(S)-4-carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl(γE-x73), (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl (γE-x74),(S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl (γE-x75),(S)-4-Carboxy-4-henicosanoylamino-butyryl (γE-x76),(S)-4-Carboxy-4-docosanoylamino-butyryl (γE-x77),(S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl (γE-x79),(S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl (γE-x80),(S)-4-Carboxy-4-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl(γE-x81), (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl (γE-x82),(S)-4-Carboxy-4-icosanoylamino-butyryl (γE-x95),(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl(γE-γE-x53),(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl(γE-γE-x70), and 3-(3-Octadecanoylamino-propionylamino)-propionyl(β-Ala-β-Ala-x70).

In some embodiments, X14 is Lys functionalized with C(O)—R⁵, which isselected from the group consisting of(S)-4-carboxy-4-hexadecanoylamino-butyryl (γE-x53),(S)-4-carboxy-4-octadecanoylamino-butyryl (γE-x70),(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl(γE-γE-x70), 4-octadecanoylamino-butyryl (GABA-x70),(S)-4-Carboxy-4-henicosanoylamino-butyryl (γE-x76), and3-(3-Octadecanoylamino-propionylamino)-propionyl (β-Ala-β-Ala-x70).

A further embodiment relates to a group of compounds, wherein

-   -   R¹ is NH₂,    -   R² is NH₂ or    -   R¹ and R² are NH₂.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, wherein R⁵ is as described above,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Glu, Ile, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala, Arg,        Aib, Leu, Lys and Tyr,    -   X19 represents an amino acid residue selected from Ala, Gln, Val        and Aib,    -   X20 represents an amino acid residue selected from Gln, Aib,        Phe, Arg, Leu, Lys and His,    -   X21 represents an amino acid residue selected from Asp, Glu,        Tyr, and Leu,    -   X28 represents an amino acid residue selected from Asn, Ala,        Aib, Arg and Lys,    -   X29 represents an amino acid residue selected from Gly, Thr,        Aib, D-Ala and Ala,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, wherein R⁵ is as described above,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Glu, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala, Arg,        Aib, Leu and Tyr,    -   X19 represents an amino acid residue selected from Ala, Val and        Aib,    -   X20 represents an amino acid residue selected from Gln, Aib,        Phe, Leu, Lys, His, Pip, (S)MeLys, (R)MeLys and (S)MeOrn,    -   X21 represents an amino acid residue selected from Asp, Glu and        Leu,    -   X28 represents an amino acid residue selected from Asn, Ala, Aib        and Ser,    -   X29 represents an amino acid residue selected from Gly, Thr,        Aib, D-Ala and Ala,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents Ile,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, wherein R⁵ is as described above,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Glu, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala and Arg,    -   X19 represents an amino acid residue selected from Ala and Val,    -   X20 represents an amino acid residue selected from Gln, Aib,        Lys, Pip, (S)MeLys, (R)MeLys and (S)MeOrn and His,    -   X21 represents an amino acid residue selected from Asp, Glu and        Leu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly, Thr and        D-Ala,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, Glu and        His,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents an amino acid residue having a side chain with an        —NH₂ group, wherein the —NH₂ side chain group is functionalized        by —C(O)—R⁵, wherein R⁵ is as described above,    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Lys,        Glu, Gln, Leu, Aib, Tyr and Ala,    -   X18 represents an amino acid residue selected from Ala and Arg,    -   X19 represents an amino acid residue selected from Ala and Val,    -   X20 represents an amino acid residue selected from Gln, Aib, Lys        and His,    -   X21 represents an amino acid residue selected from Asp, Glu and        Leu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly, Thr and        D-Ala,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln and Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,        3-(3-Octadecanoylamino-propionylamino)-propionyl- and        4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-henicosanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,        3-(3-Octadecanoylamino-propionylamino)-propionyl- and        4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-henicosanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents Gln,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,        3-(3-Octadecanoylamino-propionylamino)-propionyl- and        4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-henicosanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        4-octadecanoylamino-butyryl-, Hexadecanoyl-,        (S)-4-Carboxy-4-henicosanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,        3-(3-Octadecanoylamino-propionylamino)-propionyl-.

A further embodiment relates to a group of compounds, wherein

-   -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,        4-octadecanoylamino-butyryl-,        (S)-4-Carboxy-4-henicosanoylamino-butyryl-,        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,        3-(3-Octadecanoylamino-propionylamino)-propionyl-.

A further embodiment relates to a group of compounds, wherein

-   -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,        (S)-4-Carboxy-4-octadecanoylamino-butyryl-.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln and Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, His and        Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents Glu,    -   X16 represents an amino acid residue selected from Glu and Lys,    -   X17 represents Glu,    -   X18 represents Ala,    -   X19 represents Val,    -   X20 represents Arg,    -   X21 represents Leu,    -   X28 represents an amino acid residue selected from Asn, Aib and        Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents Glu,    -   X16 represents an amino acid residue selected from Glu and Lys,    -   X17 represents Glu,    -   X18 represents Ala,    -   X19 represents Val,    -   X20 represents Arg,    -   X21 represents Leu,    -   X28 represents an amino acid residue selected from Asn, Aib and        Ala,    -   X29 represents Gly,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, His and        Glu,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents Glu,    -   X17 represents an amino acid residue selected from Arg and Gln,    -   X18 represents an amino acid residue selected from Ala and Arg,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Pip,        (S)MeLys, (R)MeLys and (S)MeOrn,    -   X21 represents Glu,    -   X28 represents an amino acid residue selected from Asn, Ser and        Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, His and        Glu,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, hexadecanoyl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser, Lys, Glu        and Gln,    -   X17 represents an amino acid residue selected from Arg, Leu,        Aib, Tyr, Glu, Ala and Lys,    -   X18 represents an amino acid residue selected from Ala, Aib, Leu        and Tyr,    -   X19 represents an amino acid residue selected from Ala, Val and        Aib,    -   X20 represents Aib,    -   X21 represents an amino acid residue selected from Glu, Leu and        Tyr,    -   X28 represents an amino acid residue selected from Asn, Arg and        Ala,    -   X29 represents an amino acid residue selected from Gly, Ala,        D-Ala and Thr,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln, His and        Glu,    -   X12 represents an amino acid residue selected from Ile and Lys,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by one of the groups selected from        (S)-4-Carboxy-4-hexadecanoylamino-butyryl- and        (S)-4-Carboxy-4-octadecanoylamino-butyryl-,    -   X15 represents an amino acid residue selected from Glu and Asp,    -   X16 represents an amino acid residue selected from Ser, Lys and        Glu,    -   X17 represents an amino acid residue selected from Arg, Lys,        Ile, Glu and Gln,    -   X18 represents an amino acid residue selected from Ala, Arg and        Lys,    -   X19 represents an amino acid residue selected from Ala, Val and        Gln,    -   X20 represents an amino acid residue selected from Gln, Phe,        Leu, Lys, His and Arg,    -   X21 represents an amino acid residue selected from Glu, Asp and        Leu,    -   X28 represents an amino acid residue selected from Asn, Arg, Lys        and Ala,    -   X29 represents an amino acid residue selected from Gly, Aib and        Thr,    -   X40 is either absent or represents Lys.

A further embodiment relates to a group of compounds, wherein

-   -   X12 represents Ile.

A further embodiment relates to a group of compounds, wherein

-   -   X19 represents Ala.

A further embodiment relates to a group of compounds, wherein

-   -   X16 represents Glu,    -   X20 represents an amino acid residue selected from Pip,        (S)MeLys, (R)MeLys and (S)MeOrn.

A further embodiment relates to a group of compounds, wherein

-   -   X28 represents Ala,    -   X29 represents Gly.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln and Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by —C(O)—R⁵, which is selected from the group        consisting of        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-x53),        (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-x70),        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-(γE-γE-x70),        3-(3-Octadecanoylamino-propionylamino)-propionyl-(βA-βA-x70),        4-octadecanoylamino-butyryl-(GABA-x70), and        (S)-4-Carboxy-4-henicosanoylamino-butyryl-(γE-x76),    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents an amino acid residue selected from Gln and Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by —C(O)—R⁵, which is        (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-x53),    -   X15 represents an amino acid residue selected from Asp and Glu,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents an amino acid residue selected from Asp and Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

A further embodiment relates to a group of compounds, wherein

-   -   X3 represents Glu,    -   X12 represents Ile,    -   X14 represents Lys, wherein the —NH₂ side chain group is        functionalized by —C(O)—R⁵, which is selected from the group        consisting of        (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-x70),        (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-(γE-γE-x70),        3-(3-Octadecanoylamino-propionylamino)-propionyl-(βA-βA-x70),        4-octadecanoylamino-butyryl-(GABA-x70), and        (S)-4-Carboxy-4-henicosanoylamino-butyryl-(γE-x76),    -   X15 represents Glu,    -   X16 represents an amino acid residue selected from Ser and Lys,    -   X17 represents Arg,    -   X18 represents Ala,    -   X19 represents Ala,    -   X20 represents an amino acid residue selected from Gln and Aib,    -   X21 represents Glu,    -   X28 represents an amino acid residue selected from Asn and Ala,    -   X29 represents an amino acid residue selected from Gly and Thr,    -   X40 is absent.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 8-39 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 8-10 and 12-38 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 8-13 and 39 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 8-10 and 12-13 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 14-21 as well as salts and solvates thereof.

Specific examples of peptidic compounds of formula (I) are the compoundsof SEQ ID NO: 22-38 as well as salts and solvates thereof.

In certain embodiments, i.e. when the compound of formula (I) comprisesgenetically encoded amino acid residues, the invention further providesa nucleic acid (which may be DNA or RNA) encoding said compound, anexpression vector comprising such a nucleic acid, and a host cellcontaining such a nucleic acid or expression vector.

In a further aspect, the present invention provides a compositioncomprising a compound of the invention in admixture with a carrier. Inpreferred embodiments, the composition is a pharmaceutically acceptablecomposition and the carrier is a pharmaceutically acceptable carrier.The compound of the invention may be in the form of a salt, e.g. apharmaceutically acceptable salt or a solvate, e.g. a hydrate. In stilla further aspect, the present invention provides a composition for usein a method of medical treatment, particularly in human medicine.

In certain embodiments, the nucleic acid or the expression vector may beused as therapeutic agents, e.g. in gene therapy.

The compounds of formula (I) are suitable for therapeutic applicationwithout an additionally therapeutically effective agent. In otherembodiments, however, the compounds are used together with at least oneadditional therapeutically active agent, as described in “combinationtherapy”.

The compounds of formula (I) are particularly suitable for the treatmentor prevention of diseases or disorders caused by, associated with and/oraccompanied by disturbances in carbohydrate and/or lipid metabolism,e.g. for the treatment or prevention of hyperglycemia, type 2 diabetes,impaired glucose tolerance, type 1 diabetes, obesity and metabolicsyndrome. Further, the compounds of the invention are particularlysuitable for the treatment or prevention of degenerative diseases,particularly neurodegenerative diseases.

The compounds described find use, inter alia, in preventing weight gainor promoting weight loss. By “preventing” is meant inhibiting orreducing when compared to the absence of treatment, and is notnecessarily meant to imply complete cessation of a disorder.

The compounds of the invention may cause a decrease in food intakeand/or increase in energy expenditure, resulting in the observed effecton body weight.

Independently of their effect on body weight, the compounds of theinvention may have a beneficial effect on circulating cholesterollevels, being capable of improving lipid levels, particularly LDL, aswell as HDL levels (e.g. increasing HDL/LDL ratio).

Thus, the compounds of the invention can be used for direct or indirecttherapy of any condition caused or characterised by excess body weight,such as the treatment and/or prevention of obesity, morbid obesity,obesity linked inflammation, obesity linked gallbladder disease, obesityinduced sleep apnea. They may also be used for treatment and preventionof the metabolic syndrome, diabetes, hypertension, atherogenicdyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease,or stroke. Their effects in these conditions may be as a result of orassociated with their effect on body weight, or may be independentthereof.

Preferred medical uses include delaying or preventing diseaseprogression in type 2 diabetes, treating metabolic syndrome, treatingobesity or preventing overweight, for decreasing food intake, increaseenergy expenditure, reducing body weight, delaying the progression fromimpaired glucose tolerance (IGT) to type 2 diabetes; delaying theprogression from type 2 diabetes to insulin-requiring diabetes;regulating appetite; inducing satiety; preventing weight regain aftersuccessful weight loss; treating a disease or state related tooverweight or obesity; treating bulimia; treating binge eating; treatingatherosclerosis, hypertension, type 2 diabetes, IGT, dyslipidemia,coronary heart disease, hepatic steatosis, treatment of beta-blockerpoisoning, use for inhibition of the motility of the gastrointestinaltract, useful in connection with investigations of the gastrointestinaltract using techniques such as X-ray, CT- and NMR-scanning.

Further preferred medical uses include treatment or prevention ofdegenerative disorders, particularly neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, Huntington's disease, ataxia,e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewybody dementia, multi-systemic atrophy, amyotrophic lateral sclerosis,primary lateral sclerosis, spinal muscular atrophy, prion-associateddiseases, e.g. Creutzfeldt-Jacob disease, multiple sclerosis,telangiectasia, Batten disease, corticobasal degeneration, subacutecombined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease,toxic encephalopathy, infantile Refsum disease, Refsum disease,neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Josephdisease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehogsyndrome, proteopathy, cerebral β-amyloid angiopathy, retinal ganglioncell degeneration in glaucoma, synucleinopathies, tauopathies,frontotemporal lobar degeneration (FTLD), dementia, cadasil syndrome,hereditary cerebral hemorrhage with amyloidosis, Alexander disease,seipinopathies, familial amyloidotic neuropathy, senile systemicamyloidosis, serpinopathies, AL (light chain) amyloidosis (primarysystemic amyloidosis), AH (heavy chain) amyloidosis, AA (secondary)amyloidosis, aortic medial amyloidosis, ApoAI amyloidosis, ApoAIIamyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnishtype (FAF), Lysozyme amyloidosis, Fibrinogen amyloidosis, Dialysisamyloidosis, Inclusion body myositis/myopathy, Cataracts, Retinitispigmentosa with rhodopsin mutations, medullary thyroid carcinoma,cardiac atrial amyloidosis, pituitary prolactinoma, Hereditary latticecorneal dystrophy, Cutaneous lichen amyloidosis, Mallory bodies, corneallactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic(Pindborg) tumor amyloid, cystic fibrosis, sickle cell disease orcritical illness myopathy (CIM).

Further medical uses include treatment of bone related disorders, suchas osteoporosis or osteoarthritis, etc., where increased bone formationand decreased bone resorption might be beneficial.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The amino acid sequences of the present invention contain theconventional one letter and three letter codes for naturally occurringamino acids, as well as generally accepted three letter codes for otheramino acids, such as Aib (α-aminoisobutyric acid), Orn (ornithin), Dab(2,4-diamino butyric acid), Dap (2,3-diamino propionic acid), Nle(norleucine), GABA (γ-aminobutyric acid) or Ahx (ε-aminohexanoic acid).

Furthermore, the following codes were used for the amino acids shown inTable 4:

TABLE 4 structure name code

  (S)MeLys (S)-α-methyl-lysine (S)MeLys

  (R)MeLys (R)-α-methyl-lysine (R)MeLys

  (S)MeOrn (S)-α-methyl- ornithin (S)MeOrn

  Pip 4-amino-piperidine- 4-carboxylic acid Pip

The term “native exendin-4” refers to native exendin-4 having thesequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH₂ (SEQ ID NO: 1).

The invention provides peptidic compounds as defined above.

The peptidic compounds of the present invention comprise a linearbackbone of amino carboxylic acids linked by peptide, i.e. carboxamidebonds. Preferably, the amino carboxylic acids are α-amino carboxylicacids and more preferably L-α-amino carboxylic acids, unless indicatedotherwise. The peptidic compounds preferably comprise a backbonesequence of 39-40 amino carboxylic acids.

The peptidic compounds of the present invention may have unmodifiedside-chains, but carry at least one modification at one of the sidechains.

For the avoidance of doubt, in the definitions provided herein, it isgenerally intended that the sequence of the peptidic moiety (II) differsfrom native exendin-4 at least at one of those positions which arestated to allow variation. Amino acids within the peptide moiety (II)can be considered to be numbered consecutively from 0 to 40 in theconventional N-terminal to C-terminal direction. Reference to a“position” within peptidic moiety (II) should be constructedaccordingly, as should reference to positions within native exendin-4and other molecules, e.g., in exendin-4, His is at position 1, Gly atposition 2, . . . , Met at position 14, . . . and Ser at position 39.

The amino acid residues at position 14 and optionally at position 40,having a side chain with an —NH₂ group, e.g. Lys, Orn, Dab or Dap areconjugated to a functional group, e.g. acyl groups. Thus, one or moreselected amino acids of the peptides in the present invention may carrya covalent attachment at their side chains. In some cases thoseattachments may be lipophilic. These lipophilic side chain attachmentshave the potential to reduce in vivo clearance of the peptides thusincreasing their in vivo half-lives.

The lipophilic attachment may consist of a lipophilic moiety which canbe a branched or unbranched, aliphatic or unsaturated acyclic moietyand/or a cyclic moiety selected from one or several aliphatic orunsaturated homocycles or heterocycles, aromatic condensed ornon-condensed homocycles or heterocycles, ether linkages, unsaturatedbonds and substituents, e.g. hydroxy and/or carboxy groups. Thelipophilic moiety may be attached to the peptide either by alkylation,reductive amination or by an amide bond, a carbamate or a sulfonamidebond in case of amino acids carrying an amino group at their side chain.

Nonlimiting examples of lipophilic moieties that can be attached toamino acid side chains include fatty acids, e.g. C₈₋₃₀ fatty acids suchas palmitic acid, myristic acid, stearic acid and oleic acid, and/orcyclic groups as described above or derivatives thereof.

There might be one or several linkers between the amino acid of thepeptide and the lipophilic attachment. Nonlimiting examples of thoselinkers are β-alanine, γ-glutamic acid, α-glutamic acid, γ-aminobutyricacid and/or ε-aminohexanoic acid or dipeptides, such asp-Ala-β-Ala (alsoabbreviated βA-βA herein) and/or γ-Glu-γ-Glu (also abbreviated γE-γEherein) in all their stereo-isomer forms (S and R enantiomers).

Thus, one nonlimiting example of a side chain attachment is palmiticacid which is covalently linked to the α-amino group of glutamic acidforming an amide bond. The γ-carboxy group of this substituted glutamicacid can form an amide bond with the side chain amino group of a lysinewithin the peptide.

In a further aspect, the present invention provides a compositioncomprising a compound of the invention as described herein, or a salt orsolvate thereof, in admixture with a carrier.

The invention also provides the use of a compound of the presentinvention for use as a medicament, particularly for the treatment of acondition as described below.

The invention also provides a composition wherein the composition is apharmaceutically acceptable composition, and the carrier is apharmaceutically acceptable carrier.

Peptide Synthesis

The skilled person is aware of a variety of different methods to preparethe peptides that are described in this invention. These methods includebut are not limited to synthetic approaches and recombinant geneexpression. Thus, one way of preparing these peptides is the synthesisin solution or on a solid support and subsequent isolation andpurification. A different way of preparing the peptides is geneexpression in a host cell in which a DNA sequence encoding the peptidehas been introduced. Alternatively, the gene expression can be achievedwithout utilizing a cell system. The methods described above may also becombined in any way.

A preferred way to prepare the peptides of the present invention issolid phase synthesis on a suitable resin. Solid phase peptide synthesisis a well established methodology (see for example: Stewart and Young,Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, Ill.,1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. APractical Approach, Oxford-IRL Press, New York, 1989). Solid phasesynthesis is initiated by attaching an N-terminally protected amino acidwith its carboxy terminus to an inert solid support carrying a cleavablelinker. This solid support can be any polymer that allows coupling ofthe initial amino acid, e.g. a trityl resin, a chlorotrityl resin, aWang resin or a Rink resin in which the linkage of the carboxy group (orcarboxamide for Rink resin) to the resin is sensitive to acid (when Fmocstrategy is used). The polymer support must be stable under theconditions used to deprotect the α-amino group during the peptidesynthesis.

After the first amino acid has been coupled to the solid support, theα-amino protecting group of this amino acid is removed. The remainingprotected amino acids are then coupled one after the other in the orderrepresented by the peptide sequence using appropriate amide couplingreagents, for example BOP, HBTU, HATU or DIC(N,N′-diisopropylcarbodiimide)/HOBt (1-hydroxybenzotriazol), whereinBOP, HBTU and HATU are used with tertiary amine bases. Alternatively,the liberated N-terminus can be functionalized with groups other thanamino acids, for example carboxylic acids, etc.

Usually, reactive side-chain groups of the amino acids are protectedwith suitable blocking groups. These protecting groups are removed afterthe desired peptides have been assembled. They are removed concomitantlywith the cleavage of the desired product from the resin under the sameconditions. Protecting groups and the procedures to introduce protectinggroups can be found in Protective Groups in Organic Synthesis, 3d ed.,Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999).

In some cases it might be desirable to have side-chain protecting groupsthat can selectively be removed while other side-chain protecting groupsremain intact. In this case the liberated functionality can beselectively functionalized. For example, a lysine may be protected withan ivDde ([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl)protecting group (S. R. Chhabra et al., Tetrahedron Lett. 39, (1998),1603) which is labile to a very nucleophilic base, for example 4%hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal aminogroup and all side-chain functionalities are protected with acid labileprotecting groups, the ivDde group can be selectively removed using 4%hydrazine in DMF and the corresponding free amino group can then befurther modified, e.g. by acylation. The lysine can alternatively becoupled to a protected amino acid and the amino group of this amino acidcan then be deprotected resulting in another free amino group which canbe acylated or attached to further amino acids.

Finally the peptide is cleaved from the resin. This can be achieved byusing King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J.Peptide Protein Res. 36, 1990, 255-266). The raw material can then bepurified by chromatography, e.g. preparative RP-HPLC, if necessary.

Potency

As used herein, the term “potency” or “in vitro potency” is a measurefor the ability of a compound to activate the receptors for GLP-1, GIPor glucagon in a cell-based assay. Numerically, it is expressed as the“EC₅₀ value”, which is the effective concentration of a compound thatinduces a half maximal increase of response (e.g. formation ofintracellular cAMP) in a dose-response experiment.

Therapeutic Uses

The compounds of the invention are agonists for the receptors for GLP-1and for GIP as well as optionally the glucagon receptor (e.g. “dual ortrigonal agonists”). Such peptides that are GIP/GLP-1 co-agonists, orGIP/GLP-1/glucagon tri-agonists may provide therapeutic benefit toaddress a clinical need for targeting the metabolic syndrome by allowingsimultaneous treatment of diabetes and obesity.

Metabolic syndrome is a combination of medical disorders that, whenoccurring together, increase the risk of developing type 2 diabetes, aswell as atherosclerotic vascular disease, e.g. heart disease and stroke.Defining medical parameters for the metabolic syndrome include diabetesmellitus, impaired glucose tolerance, raised fasting glucose, insulinresistance, urinary albumin secretion, central obesity, hypertension,elevated triglycerides, elevated LDL cholesterol and reduced HDLcholesterol.

Obesity is a medical condition in which excess body fat has accumulatedto the extent that it may have an adverse effect on health and lifeexpectancy and due to its increasing prevalence in adults and childrenit has become one of the leading preventable causes of death in modernworld. It increases the likelihood of various other diseases, includingheart disease, type 2 diabetes, obstructive sleep apnea, certain typesof cancer, as well as osteoarthritis, and it is most commonly caused bya combination of excess food intake, reduced energy expenditure, as wellas genetic susceptibility.

Diabetes mellitus, often simply called diabetes, is a group of metabolicdiseases in which a person has high blood sugar levels, either becausethe body does not produce enough insulin, or because cells do notrespond to the insulin that is produced. The most common types ofdiabetes are: (1) type 1 diabetes, where the body fails to produceinsulin; (2) type 2 diabetes, where the body fails to use insulinproperly, combined with an increase in insulin deficiency over time, and(3) gestational diabetes, where women develop diabetes due to theirpregnancy. All forms of diabetes increase the risk of long-termcomplications, which typically develop after many years. Most of theselong-term complications are based on damage to blood vessels and can bedivided into the two categories “macrovascular” disease, arising fromatherosclerosis of larger blood vessels and “microvascular” disease,arising from damage of small blood vessels. Examples for macrovasculardisease conditions are ischemic heart disease, myocardial infarction,stroke and peripheral vascular disease. Examples for microvasculardiseases are diabetic retinopathy, diabetic nephropathy, as well asdiabetic neuropathy.

The receptors for GLP-1 and GIP as well as glucagon are members of thefamily of 7-transmembrane-spanning, heterotrimeric G-protein coupledreceptors. They are structurally related to each other and share notonly a significant level of sequence identity, but have also similarmechanisms of ligand recognition and intracellular signaling pathways.

Similarly, the peptides GLP-1, GIP and glucagon share regions of highsequence identity/similarity. GLP-1 and glucagon are produced from acommon precursor, preproglucagon, which is differentially processed in atissue-specific manner to yield e.g. GLP-1 in intestinal endocrine cellsand glucagon in alpha cells of pancreatic islets. GIP is derived from alarger proGIP prohormone precursor and is synthesized and released fromK-cells located in the small intestine.

The peptidic incretin hormones GLP-1 and GIP are secreted by intestinalendocrine cells in response to food and account for up to 70% ofmeal-stimulated insulin secretion. Evidence suggests that GLP-1secretion is reduced in subjects with impaired glucose tolerance or type2 diabetes, whereas responsiveness to GLP-1 is still preserved in thesepatients. Thus, targeting of the GLP-1 receptor with suitable agonistsoffers an attractive approach for treatment of metabolic disorders,including diabetes. The receptor for GLP-1 is distributed widely, beingfound mainly in pancreatic islets, brain, heart, kidney and thegastrointestinal tract. In the pancreas, GLP-1 acts in a strictlyglucose-dependent manner by increasing secretion of insulin from betacells. This glucose-dependency shows that activation of GLP-1 receptorsis unlikely to cause hypoglycemia. Also the receptor for GIP is broadlyexpressed in peripheral tissues including pancreatic islets, adiposetissue, stomach, small intestine, heart, bone, lung, kidney, testis,adrenal cortex, pituitary, endothelial cells, trachea, spleen, thymus,thyroid and brain. Consistent with its biological function as incretinhormone, the pancreatic β-cell express the highest levels of thereceptor for GIP in humans. There is some clinical evidence that theGIP-receptor mediated signaling could be impaired in patients with T2DMbut GIP-action is shown to be reversible and could be restored withimprovement of the diabetic status. Of note, the stimulation of insulinsecretion by both incretin hormones, GIP and GLP-1 is strictlyglucosed-dependent ensuring a fail-safe mechanism associated with at lowrisk for hypoglycemia.

At the beta cell level, GLP-1 and GIP have been shown to promote glucosesensitivity, neogenesis, proliferation, transcription of proinsulin andhypertrophy, as well as antiapoptosis. A peptide with dual agonisticactivity for the GLP-1 and the GIP receptor could be anticipated to haveadditive or synergistic anti-diabetic benefit. Other relevant effects ofGLP-1 beyond the pancreas include delayed gastric emptying, increasedsatiety, decreased food intake, reduction of body weight, as well asneuroprotective and cardioprotective effects. In patients with type 2diabetes, such extrapancreatic effects could be particularly importantconsidering the high rates of comorbidities like obesity andcardiovascular disease. Further GIP actions in peripheral tissues beyondthe pancreas comprise increased bone formation and decreased boneresorption as well as neuroprotective effects which might be beneficialfor the treatment of osteoporosis and cognitive defects like Alzheimer'sdisease.

Glucagon is a 29 amino acid peptide hormone that is produced bypancreatic alpha cells and released into the bloodstream whencirculating glucose is low. An important physiological role of glucagonis to stimulate glucose output in the liver, which is a processproviding the major counterregulatory mechanism for insulin inmaintaining glucose homeostasis in vivo.

Glucagon receptors are however also expressed in extra-hepatic tissuessuch as kidney, heart, adipocytes, lymphoblasts, brain, retina, adrenalgland and gastrointestinal tract, suggesting a broader physiologicalrole beyond glucose homeostasis. Accordingly, recent studies havereported that glucagon has therapeutically positive effects on energymanagement, including stimulation of energy expenditure andthermogenesis, accompanied by reduction of food intake and body weightloss. Altogether, stimulation of glucagon receptors might be useful inthe treatment of obesity and the metabolic syndrome.

Oxyntomodulin is a peptide hormone consisting of glucagon with an eightamino acids encompassing C-terminal extension. Like GLP-1 and glucagon,it is preformed in preproglucagon and cleaved and secreted in atissue-specific manner by endocrinal cells of the small bowel.Oxyntomodulin is known to stimulate both, the receptors for GLP-1 andglucagon and is therefore the prototype of a dual agonist.

As GLP-1 and GIP are known for their anti-diabetic effects, GLP-1 andglucagon are both known for their food intake-suppressing effects andglucagon is also a mediator of additional energy expenditure, it isconceivable that a combination of the activities of the two or threehormones in one molecule can yield a powerful medication for treatmentof the metabolic syndrome and in particular its components diabetes andobesity.

Accordingly, the compounds of the invention may be used for treatment ofglucose intolerance, insulin resistance, pre-diabetes, increased fastingglucose, type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis,coronary heart disease, peripheral artery disease, stroke or anycombination of these individual disease components.

In addition, they may be used for control of appetite, feeding andcalory intake, increase of energy expenditure, prevention of weightgain, promotion of weight loss, reduction of excess body weight andaltogether treatment of obesity, including morbid obesity.

Further disease states and health conditions which could be treated withthe compounds of the invention are obesity-linked inflammation,obesity-linked gallbladder disease and obesity-induced sleep apnea.

Although all these conditions could be associated directly or indirectlywith obesity, the effects of the compounds of the invention may bemediated in whole or in part via an effect on body weight, orindependent thereof.

Further, diseases to be treated are osteoporosis and neurodegenerativediseases such as Alzheimer's disease or Parkinson's disease, or otherdegenerative diseases as described above.

Compared to GLP-1, glucagon and oxyntomodulin, exendin-4 has beneficialphysicochemical properties, such as solubility and stability in solutionand under physiological conditions (including enzymatic stabilitytowards degradation by enzymes, such as DPP-4 or NEP), which results ina longer duration of action in vivo. Therefore, exendin-4 might serve asgood starting scaffold to obtain exendin-4 analogues with dual or eventriple pharmacologies, e.g., GLP-1/GIP and optionally in additionglucagon agonism.

Nevertheless, also exendin-4 has been shown to be chemically labile dueto methionine oxdiation in position 14 as well as deamidation andisomerization of asparagine in position 28. Therefore, stability mightbe further improved by substitution of methionine at position 14 and theavoidance of sequences that are known to be prone to degradation viaaspartimide formation, especially Asp-Gly or Asn-Gly at positions 28 and29.

Pharmaceutical Compositions

The term “pharmaceutical composition” indicates a mixture containingingredients that are compatible when mixed and which may beadministered. A pharmaceutical composition may include one or moremedicinal drugs. Additionally, the pharmaceutical composition mayinclude carriers, buffers, acidifying agents, alkalizing agents,solvents, adjuvants, tonicity adjusters, emollients, expanders,preservatives, physical and chemical stabilizers e.g. surfactants,antioxidants and other components, whether these are considered activeor inactive ingredients. Guidance for the skilled in preparingpharmaceutical compositions may be found, for example, in Remington: TheScience and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R.,2000, Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed),Handbook of Pharmaceutical Excipients, PhP, May 2013 update.

The exendin-4 peptide derivatives of the present invention, or saltsthereof, are administered in conjunction with an acceptablepharmaceutical carrier, diluent, or excipient as part of apharmaceutical composition. A “pharmaceutically acceptable carrier” is acarrier which is physiologically acceptable (e.g. physiologicallyacceptable pH) while retaining the therapeutic properties of thesubstance with which it is administered. Standard acceptablepharmaceutical carriers and their formulations are known to one skilledin the art and described, for example, in Remington: The Science andPractice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000,Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed), Handbook ofPharmaceutical excipients, PhP, May 2013 update. One exemplarypharmaceutically acceptable carrier is physiological saline solution.

In one embodiment carriers are selected from the group of buffers (e.g.citrate/citric acid), acidifying agents (e.g. hydrochloric acid),alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol),co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g.mannitol), stabilizers (e.g. surfactant, antioxidants, amino acids).

Concentrations used are in a range that is physiologically acceptable.

Acceptable pharmaceutical carriers or diluents include those used informulations suitable for oral, rectal, nasal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, and transdermal)administration. The compounds of the present invention will typically beadministered parenterally.

The term “pharmaceutically acceptable salt” means salts of the compoundsof the invention which are safe and effective for use in mammals.Pharmaceutically acceptable salts may include, but are not limited to,acid addition salts and basic salts. Examples of acid addition saltsinclude chloride, sulfate, hydrogen sulfate, (hydrogen) phosphate,acetate, citrate, tosylate or mesylate salts. Examples of basic saltsinclude salts with inorganic cations, e.g. alkaline or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts andsalts with organic cations such as amine salts. Further examples ofpharmaceutically acceptable salts are described in Remington: TheScience and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R.,2000, Lippencott Williams & Wilkins or in Handbook of PharmaceuticalSalts, Properties, Selection and Use, e.d. P. H. Stahl, C. G. Wermuth,2002, jointly published by Verlag Helvetica Chimica Acta, Zurich,Switzerland, and Wiley-VCH, Weinheim, Germany.

The term “solvate” means complexes of the compounds of the invention orsalts thereof with solvent molecules, e.g. organic solvent moleculesand/or water.

In the pharmaceutical composition, the exendin-4 derivative can be inmonomeric or oligomeric form.

The term “therapeutically effective amount” of a compound refers to anontoxic but sufficient amount of the compound to provide the desiredeffect. The amount of a compound of the formula I necessary to achievethe desired biological effect depends on a number of factors, forexample the specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. An appropriate“effective” amount in any individual case may be determined by one ofordinary skill in the art using routine experimentation For example the“therapeutically effective amount” of a compound of the formula (I) isabout 0.01 to 50 mg/dose, preferably 0.1 to 10 mg/dose.

Pharmaceutical compositions of the invention are those suitable forparenteral (for example subcutaneous, intramuscular, intradermal orintravenous), oral, rectal, topical and peroral (for example sublingual)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case.

Suitable pharmaceutical compositions may be in the form of separateunits, for example capsules, tablets and powders in vials or ampoules,each of which contains a defined amount of the compound; as powders orgranules; as solution or suspension in an aqueous or nonaqueous liquid;or as an oil-in-water or water-in-oil emulsion. It may be provided insingle or multiple dose injectable form, for example in the form of apen. The compositions may, as already mentioned, be prepared by anysuitable pharmaceutical method which includes a step in which the activeingredient and the carrier (which may consist of one or more additionalingredients) are brought into contact.

In certain embodiments the pharmaceutical composition may be providedtogether with a device for application, for example together with asyringe, an injection pen or an autoinjector. Such devices may beprovided separate from a pharmaceutical composition or prefilled withthe pharmaceutical composition.

Combination Therapy

The compounds of the present invention, dual agonists for the GLP-1 andglucagon receptors, can be widely combined with other pharmacologicallyactive compounds, such as all drugs mentioned in the Rote Liste 2012and/or the Rote Liste 2013, e.g. with all antidiabetics mentioned in theRote Liste 2012, chapter 12, and/or the Rote Liste 2013, chapter 12, allweight-reducing agents or appetite suppressants mentioned in the RoteListe 2012, chapter 1, and/or the Rote Liste 2013, chapter 1, alllipid-lowering agents mentioned in the Rote Liste 2012, chapter 58,and/or the Rote Liste 2013, chapter 58, all antihypertensives andnephroprotectives, mentioned in the Rote Liste 2012 and/or the RoteListe 2013, or all diuretics mentioned in the Rote Liste 2012, chapter36, and/or the Rote Liste 2013, chapter 36.

The active ingredient combinations can be used especially for asynergistic improvement in action. They can be applied either byseparate administration of the active ingredients to the patient or inthe form of combination products in which a plurality of activeingredients are present in one pharmaceutical preparation. When theactive ingredients are administered by separate administration of theactive ingredients, this can be done simultaneously or successively.

Most of the active ingredients mentioned hereinafter are disclosed inthe USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2011.

Other active substances which are suitable for such combinations includein particular those which for example potentiate the therapeutic effectof one or more active substances with respect to one of the indicationsmentioned and/or which allow the dosage of one or more active substancesto be reduced.

Therapeutic agents which are suitable for combinations include, forexample, antidiabetic agents such as:

Insulin and Insulin derivatives, for example: Glargine/Lantus®, 270-330U/mL of insulin glargine (EP 2387989 A), 300 U/mL of insulin glargine(EP 2387989 A), Glulisin/Apidra®, Detemir/Levemir®,Lispro/Humalog®/Liprolog®, Degludec/DegludecPlus, Aspart, basal insulinand analogues (e.g. LY-2605541, LY2963016, NN1436), PEGylated insulinLispro, Humulin®, Linjeta, SuliXen®, NN1045, Insulin plus Symlin,PE0139, fast-acting and short-acting insulins (e.g. Linjeta, PH20,NN1218, HinsBet), (APC-002) hydrogel, oral, inhalable, transdermal andsublingual insulins (e.g. Exubera®, Nasulin®, Afrezza, Tregopil, TPM 02,Capsulin, Oral-lyn®, Cobalamin® oral insulin, ORMD-0801, NN1953, NN1954,NN1956, VIAtab, Oshadi oral insulin). Additionally included are alsothose insulin derivatives which are bonded to albumin or another proteinby a bifunctional linker.

GLP-1, GLP-1 analogues and GLP-1 receptor agonists, for example:Lixisenatide/AVE0010/ZP10/Lyxumia,Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993,Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide,Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide/HM-112600, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926,NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697,DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030,CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN andGlucagon-Xten.

DPP-4 inhibitors, for example: Alogliptin/Nesina,Trajenta/Linagliptin/BI-1356/Ondero/Trajenta/Tradjenta/Trayenta/Tradzenta,Saxagliptin/Onglyza,Sitagliptin/Januvia/Xelevia/Tesave/Janumet/Velmetia,Galvus/Vildagliptin, Anagliptin, Gemigliptin, Teneligliptin,Melogliptin, Trelagliptin, DA-1229, Omarigliptin/MK-3102, KM-223,Evogliptin, ARI-2243, PBL-1427, Pinoxacin.

SGLT2 inhibitors, for example: Invokana/Canaglifozin,Forxiga/Dapagliflozin, Remoglifozin, Sergliflozin, Empagliflozin,Ipragliflozin, Tofogliflozin, Luseogliflozin, LX-4211,Ertuglifozin/PF-04971729, RO-4998452, EGT-0001442, KGA-3235/DSP-3235,LIK066, SBM-TFC-039,

Biguanides (e.g. Metformin, Buformin, Phenformin), Thiazolidinediones(e.g. Pioglitazone, Rivoglitazone, Rosiglitazone, Troglitazone), dualPPAR agonists (e.g. Aleglitazar, Muraglitazar, Tesaglitazar),Sulfonylureas (e.g. Tolbutamide, Glibenclamide, Glimepiride/Amaryl,Glipizide), Meglitinides (e.g. Nateglinide, Repaglinide, Mitiglinide),Alpha-glucosidase inhibitors (e.g. Acarbose, Miglitol, Voglibose),Amylin and Amylin analogues (e.g. Pramlintide, Symlin).

GPR119 agonists (e.g. GSK-263A, PSN-821, MBX-2982, APD-597, ZYG-19,DS-8500), GPR40 agonists (e.g. Fasiglifam/TAK-875, TUG-424, P-1736,JTT-851, GW9508).

Other suitable combination partners are: Cycloset, inhibitors of11-beta-HSD (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329,HSD-016, BI-135585), activators of glucokinase (e.g. TTP-399, AMG-151,TAK-329, GKM-001), inhibitors of DGAT (e.g. LCQ-908), inhibitors ofprotein tyrosinephosphatase 1 (e.g. Trodusquemine), inhibitors ofglucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase,inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvatecarboxykinase, inhibitors of glycogen synthase kinase, inhibitors ofpyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists, SGLT-1inhibitors (e.g. LX-2761).

One or more lipid lowering agents are also suitable as combinationpartners, such as for example: HMG-CoA-reductase inhibitors (e.g.Simvastatin, Atorvastatin), fibrates (e.g. Bezafibrate, Fenofibrate),nicotinic acid and the derivatives thereof (e.g. Niacin), PPAR-(alpha,gamma or alpha/gamma) agonists or modulators (e.g. Aleglitazar),PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe), cholesterolabsorption inhibitors (e.g. Ezetimibe), Bile acid-binding substances(e.g. Cholestyramine), ileal bile acid transport inhibitors, MTPinhibitors, or modulators of PCSK9.

HDL-raising compounds such as: CETP inhibitors (e.g. Torcetrapib,Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995) orABC1 regulators.

Other suitable combination partners are one or more active substancesfor the treatment of obesity, such as for example: Sibutramine,Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists(e.g. Velneperit), beta-3-agonists, leptin or leptin mimetics, agonistsof the 5HT2c receptor (e.g. Lorcaserin), or the combinations ofbupropione/naltrexone, bupropione/zonisamide, bupropione/phentermine orpramlintide/metreleptin.

Other suitable combination partners are:

Further gastrointestinal peptides such as Peptide YY 3-36 (PYY3-36) oranalogues thereof, pancreatic polypeptide (PP) or analogues thereof.

Glucagon receptor agonists or antagonists, GIP receptor agonists orantagonists, ghrelin antagonists or inverse agonists, Xenin andanalogues thereof.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis, such as e.g.: Angiotensin IIreceptor antagonists (e.g. telmisartan, candesartan, valsartan,losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan),ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calciumantagonists, centrally acting hypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable.

In another aspect, this invention relates to the use of a compoundaccording to the invention or a physiologically acceptable salt thereofcombined with at least one of the active substances described above as acombination partner, for preparing a medicament which is suitable forthe treatment or prevention of diseases or conditions which can beaffected by binding to the receptors for GLP-1 and glucagon and bymodulating their activity. This is preferably a disease in the contextof the metabolic syndrome, particularly one of the diseases orconditions listed above, most particularly diabetes or obesity orcomplications thereof.

The use of the compounds according to the invention, or aphysiologically acceptable salt thereof, in combination with one or moreactive substances may take place simultaneously, separately orsequentially.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; if they areused at staggered times, the two active substances are given to thepatient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to a medicamentwhich comprises a compound according to the invention or aphysiologically acceptable salt of such a compound and at least one ofthe active substances described above as combination partners,optionally together with one or more inert carriers and/or diluents.

The compound according to the invention, or physiologically acceptablesalt or solvate thereof, and the additional active substance to becombined therewith may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as so-called kit-of-parts.

LEGENDS TO THE FIGURES

FIG. 1. Effect of s.c. administration of compound SEQ ID NO: 13 at 10μg/kg on gastric emptying and intestinal passage in female NMRI-mice.Data are mean+SEM.

a) Gastric emptying

b) Small intestinal passage relative to small intestinal length

FIG. 2. Effect of s.c. administration of compound SEQ ID NO: 9 at 1, 3and 10 μg/kg on gastric emptying and intestinal passage in femaleNMRI-mice. Data are mean+SEM.

a) Gastric emptying

b) Small intestinal passage relative to small intestinal length

FIG. 3a . Effect of s.c. administration of compound SEQ ID NO: 12, SEQID NO: 13 and liraglutide at 100 μg/kg on 22-hours feed intake in femaleNMRI-mice. Data are mean+SEM.

FIG. 3b . Effect of s.c. administration of compound SEQ ID NO: 9 at 3and 10 μg/kg on 22-hours feed intake in female NMRI-mice. Data aremean+SEM.

FIG. 4. Effect of s.c. administration of compound SEQ ID NO: 9 at 10, 30and 100 μg/kg on blood glucose after 6 days of treatment in femalediet-induced obese C57BL/6NCrl mice (18 weeks on high-fat diet). Dataare mean±SEM.

FIG. 5. Effect of s.c. administration of compound SEQ ID NO: 9 at 10, 30and 100 μg/kg on body weight in female diet-induced obese (DIO)C57BL/6NCrl mice (18 weeks on high-fat diet). Data are mean±SEM.

FIG. 6. Effect of s.c. administration of compound SEQ ID NO: 9 at 10, 30and 100 μg/kg on body weight in female diet-induced obese (DIO)C57BL/6NCrl mice calculated as relative change from baseline. Data aremean±SEM.

FIG. 7. Effect of s.c. administration of compound SEQ ID NO: 9 at 10, 30and 100 μg/kg on body fat content in female diet-induced obese (DIO)C57BL/6NCrl mice. Data are mean±SEM.

FIG. 8. Effect of acute s.c. administration of compounds SEQ ID NO: 13,SEQ ID NO: 12, SEQ ID NO: 10 and SEQ ID NO: 9 at 100 μg/kg on 24 hprofile of blood glucose of diabetic db/db mice. Data are mean±SEM.

FIG. 9. Effect of once-daily s.c. administration of compound SEQ ID NO:9 at 10, 30 and 100 μg/kg on blood glucose of diabetic db/db mice after4-weeks chronic treatment. Data are mean±SEM.

FIG. 10. Effect of once-daily s.c. administration of compound SEQ ID NO:9 at 10, 30 and 100 μg/kg on HbA1c of diabetic db/db mice at start andat the end 4-weeks chronic treatment. Data are mean±SEM.

FIG. 11. Effect of s.c. administration of compound SEQ ID NO: 9 and SEQID NO: 21 at 10 μg/kg on body weight in female diet-induced obese (DIO)C57BL/6NCrl mice following 3-weeks chronic treatment once daily. Dataare mean±SEM.

FIG. 12. Effect of s.c. administration of compound SEQ ID NO: 9 and SEQID NO: 21 10 μg/kg on body weight in female diet-induced obese (DIO)C57BL/6NCrl mice following 3-weeks chronic treatment once daily. Changesin body weight were calculated as relative change from baseline. Dataare mean±SEM.

FIG. 13. Effect of 3 weeks of treatment with SEQ ID NO: 16 at 3 and 10μg/kg, s.c. and SEQ ID NO: 21 at 10 μg/kg, s.c. on non-fasted glucose indiabetic dbdb-mice, represented as change from baseline (0 mmol/l, day−7). Data are mean+SEM.

FIG. 14. Effect of 3 weeks of treatment with SEQ ID NO: 16 at 3 and 10μg/kg, s.c. and SEQ ID NO: 21 at 10 μg/kg, s.c. on HbA1c in diabeticdbdb-mice, represented as change from baseline (0%, day −7). Data aremean+SEM.

FIG. 15. Effect of 3 weeks of treatment with SEQ ID NO: 16 at 3 and 10μg/kg, s.c. and SEQ ID NO: 21 at 10 μg/kg, s.c. on oral glucosetolerance in diabetic dbdb-mice, represented as change from baseline(t=0 min, 0 mmol/l, immediately before glucose administration). Data aremean+SEM.

FIG. 16. Effect of 3 weeks of treatment with SEQ ID NO: 16 at 3 and 10μg/kg, s.c. and SEQ ID NO: 21 at 10 μg/kg, s.c. on oral glucosetolerance in diabetic dbdb-mice, represented as area under the glucosecurve (Glucose-AUC). Data are mean+SEM.

FIG. 17. Effect of treatment with SEQ ID NO: 21 at 3 μg/kg, s.c. onglucose lowering in non-fasted female diabetic dbdb-mice, represented aschange from baseline. Data are mean+SEM.

FIG. 18. Effect of treatment with SEQ ID NO: 14 at 3 μg/kg, s.c. onglucose lowering in non-fasted female diabetic dbdb-mice, represented aschange from baseline. Data are mean+SEM.

METHODS

Abbreviations employed are as follows:

-   AA amino acid-   cAMP cyclic adenosine monophosphate-   Boc tert-butyloxycarbonyl-   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   BSA bovine serum albumin-   tBu tertiary butyl-   Dde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl-   ivDde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl-   DIC N,N′-diisopropylcarbodiimide-   DIPEA N,N-diisopropylethylamine-   DMEM Dulbecco's modified Eagle's medium-   DMF dimethyl formamide-   EDT ethanedithiol-   FA formic acid-   FBS fetal bovine serum-   Fmoc fluorenylmethyloxycarbonyl-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBSS Hanks' Balanced Salt Solution-   HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium    hexafluorophosphate-   HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid-   HOBt 1-hydroxybenzotriazole-   HOSu N-hydroxysuccinimide-   HPLC High Performance Liquid Chromatography-   HTRF Homogenous Time Resolved Fluorescence-   IBMX 3-isobutyl-1-methylxanthine-   LC/MS Liquid Chromatography/Mass Spectrometry-   Palm palmitoyl-   PBS phosphate buffered saline-   PEG polyethylene glycole-   PK pharmacokinetic-   RP-HPLC reversed-phase high performance liquid chromatography-   Stea stearyl-   TFA trifluoroacetic acid-   Trt trityl-   UV ultraviolet    General Synthesis of Peptidic Compounds    Materials:

Different Rink-Amide resins(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethylresin, Merck Biosciences;4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methylresin, Agilent Technologies) were used for the synthesis of peptideamides with loadings in the range of 0.3-0.4 mmol/g.

Fmoc protected natural amino acids were purchased from ProteinTechnologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, IrisBiotech or Bachem. The following standard amino acids were usedthroughout the syntheses: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH,Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH,Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH,Fmoc-L-His(Trt)-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Met-OH, Fmoc-L-Phe-OH, Fmoc-L-Pro-OH, Fmoc-L-Ser(tBu)-OH,Fmoc-L-Thr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH,Fmoc-L-Val-OH.

In addition, the following special amino acids were purchased from thesame suppliers as above: Fmoc-L-Lys(ivDde)-OH, Fmoc-L-Lys(Mmt)-OH,Fmoc-Aib-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Ala-OH, Boc-L-Tyr(tBu)-OH,Boc-L-His(Boc)-OH (available as toluene solvate) and Boc-L-His(Trt)-OH.

The solid phase peptide syntheses were performed for example on aPrelude Peptide Synthesizer (Protein Technologies Inc) or similarautomated synthesizer using standard Fmoc chemistry and HBTU/DIPEAactivation. DMF was used as the solvent. Deprotection: 20%piperidine/DMF for 2×2.5 min. Washes: 7×DMF. Coupling: 2:5:10 200 mMAA/500 mM HBTU/2M DIPEA in DMF 2× for 20 min. Washes: 5×DMF.

In cases where a Lys-side-chain was modified, Fmoc-L-Lys(ivDde)-OH orFmoc-L-Lys(Mmt)-OH was used in the corresponding position. Aftercompletion of the synthesis, the ivDde group was removed according to amodified literature procedure (S. R. Chhabra et al., Tetrahedron Lett.39, (1998), 1603), using 4% hydrazine hydrate in DMF. The Mmt group wasremoved by repeated treatment with 1% TFA in dichloromethane. Thefollowing acylations were carried out by treating the resin with theN-hydroxy succinimide esters of the desired acid or using couplingreagents like HBTU/DIPEA or HOBt/DIC.

All the peptides that had been synthesized were cleaved from the resinwith King's cleavage cocktail consisting of 82.5% TFA, 5% phenol, 5%water, 5% thioanisole, 2.5% EDT. The crude peptides were thenprecipitated in diethyl or diisopropyl ether, centrifuged, andlyophilized. Peptides were analyzed by analytical HPLC and checked byESI mass spectrometry. Crude peptides were purified by a conventionalpreparative HPLC purification procedure.

Analytical HPLC/UPLC

Method A: Analytical UPLC/MS was performed on a Waters UPLC system witha Waters UPLC HSS 1.7 μm C18 column (2.1×100 mm) at 40° C. with agradient elution at a flow rate of 0.5 mL/min and monitored at 215 and280 nm. The gradients were set up as 10% B to 90% B over 15 min and then90% B for 1 min or as 15% B to 50% B over 12.5 min and then 50% B to 90%B over 3 min. Buffer A=0.1% formic acid in water and B=0.1% formic acidin acetonitrile. A Waters LCT Premier Time-of-Flight instrument was usedas mass analyser equipped with an electrospray in the positive ion mode.

Method B: detection at 210-225 nm, optionally coupled to a mass analyserWaters LCT Premier, electrospray positive ion mode

-   column: Waters ACQUITY UPLC® CSH™ C18 1.7 μm (150×2.1 mm) at 50° C.-   solvent: H₂O+0.5% TFA:ACN+0.35% TFA (flow 0.5 ml/min)-   gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98    (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min)

Method C: detection at 215 nm

-   column: Aeris Peptide, 3.6 μm, XB-C18 (250×4.6 mm) at 60° C.-   solvent: H₂O+0.1% TFA:ACN+0.1% TFA (flow 1.5 ml/min)-   gradient: 90:10 (0 min) to 90:10 (3 min) to 10:90 (43 min) to 10:90    (48 min) to 90:10 (49 min) to 90:10 (50 min)

Method D: detection at 214 nm

-   column: Waters X-Bridge C18 3.5 μm 2.1×150 mm-   solvent: H₂O+0.5% TFA:ACN (flow 0.55 ml/min)-   gradient: 90:10 (0 min) to 40:60 (5 min) to 1:99 (15 min)

Method E: detection at 210-225 nm, optionally coupled to a mass analyser

-   Waters LCT Premier, electrospray positive ion mode column: Waters    ACQUITY UPLC® BEH™ C18 1.7 μm (150×2.1 mm) at 50° C.-   solvent: H₂O+1% FA:ACN+1% FA (flow 0.9 ml/min)-   gradient: 95:5 (0 min) to 95:5 (2 min) to 35:65 (3 min) to 65:35    (23.5 min) to 5:95 (24 min) to 95:5 (26 min) to 95:5 (30 min)    General Preparative HPLC Purification Procedure:

The crude peptides were purified either on an Äkta Purifier System or ona Jasco semiprep HPLC System. Preparative RP-C18-HPLC columns ofdifferent sizes and with different flow rates were used depending on theamount of crude peptide to be purified. Acetonitrile+0.05 to 0.1% TFA(B) and water+0.05 to 0.1% TFA (A) were employed as eluents.Alternatively, a buffer system consisting of acetonitrile and water withminor amounts of acetic acid was used. Product-containing fractions werecollected and lyophilized to obtain the purified product, typically asTFA or acetate salt.

Solubility and Stability-Testing of Exendin-4 Derivatives

Prior to the testing of solubility and stability of a peptide batch, itscontent was determined. Therefore, two parameters were investigated, itspurity (HPLC-UV) and the amount of salt load of the batch (ionchromatography).

For solubility testing, the target concentration was 1.0 mg/mL purecompound. Therefore, solutions from solid samples were prepared indifferent buffer systems with a concentration of 1.0 mg/mL compoundbased on the previously determined content. HPLC-UV was performed after2 h of gentle agitation from the supernatant, which was obtained by 20min of centrifugation at 4000 rpm.

The solubility was then determined by comparison with the UV peak areasobtained with a stock solution of the peptide at a concentration of 2mg/mL in pure water or a variable amount of acetonitrile (opticalcontrol that all of the compound was dissolved). This analysis alsoserved as starting point (t0) for the stability testing.

For stability testing, an aliquot of the supernatant obtained forsolubility was stored for 7 days at 25° C. After that time course, thesample was centrifuged for 20 min at 4000 rpm and the supernatant wasanalysed with HPLC-UV. For determination of the amount of the remainingpeptide, the peak areas of the target compound at t0 and t7 werecompared, resulting in “% remaining peptide”, following the equation% remaining peptide=[(peak area peptide t7)×100]/peak area peptide t0.

The amount of soluble degradation products was calculated from thecomparison of the sum of the peak areas from all observed impuritiesreduced by the sum of peak areas observed at t0 (i.e. to determine theamount of newly formed peptide-related species). This value was given inpercentual relation to the initial amount of peptide at t0, followingthe equation:soluble degradation products={[(peak area sum of impurities t7)−(peakarea sum of impurities t0)]×100}/peak area peptide t0

The potential difference from the sum of “% remaining peptide” and “%soluble degradation products” to 100% reflects the amount of peptidewhich did not remain soluble upon stress conditions following theequation% precipitate=100−([% remaining peptide]+[% soluble degradationproducts])

This precipitate includes non-soluble degradation products, polymersand/or fibrils, which have been removed from analysis by centrifugation.

The chemical stability is expressed as “% remaining peptide”.

Anion Chromatography

Instrument: Dionex ICS-2000, pre/column: Ion Pac AG-18 2×50 mm(Dionex)/AS18 2×250 mm (Dionex), eluent: aqueous sodium hydroxide, flow:0.38 mL/min, gradient: 0-6 min: 22 mM KOH, 6-12 min: 22-28 mM KOH, 12-15min: 28-50 mM KOH, 15-20 min: 22 mM KOH, suppressor: ASRS 300 2 mm,detection: conductivity.

As HPLC/UPLC method D or E has been used.

In Vitro Cellular Assays for GIP Receptor, GLP-1 Receptor and GlucagonReceptor Efficacy

Agonism of compounds for the receptors was determined by functionalassays measuring cAMP response of HEK-293 cell lines stably expressinghuman GIP, GLP-1 or glucagon receptor.

cAMP content of cells was determined using a kit from Cisbio Corp. (cat.no. 62AM4PEC) based on HTRF (Homogenous Time Resolved Fluorescence). Forpreparation, cells were split into T175 culture flasks and grownovernight to near confluency in medium (DMEM/10% FBS). Medium was thenremoved and cells washed with PBS lacking calcium and magnesium,followed by proteinase treatment with accutase (Sigma-Aldrich cat. no.A6964). Detached cells were washed and resuspended in assay buffer(1×HBSS; 20 mM HEPES, 0.1% BSA, 2 mM IBMX) and cellular densitydetermined. They were then diluted to 400000 cells/ml and 25 μl-aliquotsdispensed into the wells of 96-well plates. For measurement, 25 μl oftest compound in assay buffer was added to the wells, followed byincubation for 30 minutes at room temperature. After addition of HTRFreagents diluted in lysis buffer (kit components), the plates wereincubated for 1 hr, followed by measurement of the fluorescence ratio at665/620 nm. In vitro potency of agonists was quantified by determiningthe concentrations that caused 50% activation of maximal response(EC50).

Bioanalytical Screening Method for Quantification of Exendin-4Derivatives in Mice and Pigs

Mice were dosed 1 mg/kg subcutaneously (s.c.). The mice were sacrifiedand blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 16 and 24hours post application. Plasma samples were analyzed after proteinprecipitation via liquid chromatography mass spectrometry (LC/MS). PKparameters and half-life were calculated using WinonLin Version 5.2.1(non-compartment model).

Female Göttinger minipigs were dosed 0.1 mg/kg subcutaneously (s.c.).Blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56and 72 hours post application. Plasma samples were analyzed afterprotein precipitation via liquid chromatography mass spectrometry(LC/MS). PK parameters and half-life were calculated using WinonLinVersion 5.2.1 (non-compartment model).

Gastric Emptying and Intestinal Passage in Mice

Female NMRI-mice of a body weight between 20 and 30 g were used. Micewere adapted to housing conditions for at least one week.

Mice were overnight fasted, while water remained available all the time.On the study day, mice were weighed, single-caged and allowed access to500 mg of feed for 30 min, while water was removed. At the end of themin feeding period, remaining feed was removed and weighed. Then, thetest compound/reference compound or its vehicle in the control group wasadministered subcutaneously. 60 min later, to allow the compound toreach relevant plasma exposure, a coloured, non-caloric bolus wasinstilled via gavage into the stomach. After another 30 min, the animalswere sacrificed and the stomach and the small intestine prepared. Thefilled stomach was weighed, emptied, carefully cleaned and dried andreweighed. The stomach content, calculated as weight of filledsubtracted by the weight of emptied stomach, indicated the degree ofgastric emptying. The small intestine was straightened without force andmeasured in length. Then the distance from the gastric beginning of thegut to the tip of the farthest traveled intestinal content bolus wasmeasured. The intestinal passage was given as ratio in percent of thelatter distance and the total length of the small intestine. Comparabledata can be obtained for both female and male mice.

Statistical analyses were performed with Everstat 6.0 by 1-way-ANOVA,followed by Dunnett's as post-hoc test. Dunnett's Test was applied tocompare versus vehicle control. Differences were consideredstatistically significant at the p<0.05 level.

Automated Assessment of Feed Intake in Mice

Female NMRI-mice of a body weight between 20 and 30 g were used. Micewere adapted to housing conditions for at least one week and for atleast one day single-caged in the assessment equipment, when basal datawere recorded simultaneously. On the study day, test product wasadministered subcutaneously close to the lights-off phase (12 h lightsoff) and assessment of feed consumption was directly started afterwards.Assessment included continued monitoring over 22 hours, while data areprocessed as mean over every 30 min. Repetition of this procedure overseveral days was possible. Restriction of assessment to 22 hours was forpractical reasons to allow for reweighing of animals, refilling of feedand water and drug administration between procedures. Results could beassessed as cumulated data over 22 hours or differentiated to 30 minintervals. Comparable data can be obtained for both female and malemice.

Statistical analyses were performed with Everstat 6.0 by two-way ANOVAon repeated measures and Dunnett's post-hoc analyses. Differences wereconsidered statistically significant at the p<0.05 level.

Acute and Subchronic Effects of Exendin-4 Derivatives after SubcutaneousTreatment on Blood Glucose and Body Weight in Female Diet-Induced Obese(DIO) C57BL/6NCrl Mice

18 weeks on high-fat diet (method 1)

Female C57BL/6NCrl mice were housed in groups in a specificpathogen-free barrier facility on a 12 h light/dark cycle with freeaccess to water and high-fat diet. After 18 weeks on high-fat diet, micewere stratified to treatment groups (n=8), so that each group hadsimilar mean body weight. An aged-matched group with ad libitum accessto standard chow was included as standard control group.

Before the experiment, mice were subcutaneously (s.c.) injected withvehicle solution and weighed for 3 days to acclimate them to theprocedures.

1) Acute effect on blood glucose in fed DIO mice: initial blood sampleswere taken just before first administration (s.c.) of vehicle (phosphatebuffer solution) or the exendin-4 derivatives at doses of 10, 30 and 100μg/kg (dissolved in phosphate buffer), respectively. The volume ofadministration was 5 mL/kg. The animals had access to water and theircorresponding diet during the experiment, food consumption wasdetermined at all time points of blood sampling. Blood glucose levelswere measured at t=0.5 h, t=1 h, t=2 h, t=4 h, t=6 h, t=8 h, and t=24 h(method: d-glucose hexokinase, hemolysate, AU640 Beckman Coulter). Bloodsampling was performed by tail incision without anaesthesia.

2) Subchronic effect on body weight: all animals were treated once dailys.c. in the afternoon, at the end of the light phase (12 h lights on)with either vehicle or exendin-4 derivatives at the abovementioned dosesfor 4 weeks. Body weight was recorded daily. On days 6 and 28, total fatmass was measured by nuclear magnetic resonance (NMR) using a Brukerminispec (Ettlingen, Germany).

14 weeks of prefeeding with high-fat diet (method 2)

Female C57BL/6NCrl mice were housed in groups in a specificpathogen-free barrier facility on a 12 h light/dark cycle with freeaccess to water and high-fat diet. After 14 weeks on high-fat diet, micewere stratified to treatment groups (n=8), so that each group hadsimilar mean body weight.

An aged-matched group with ad libitum access to standard chow and waterwas included as standard control group.

Before the experiment, mice were subcutaneously (s.c.) injected withvehicle solution and weighed for 3 days to acclimate them to theprocedures.

Subchronic effect on body weight: all animals were treated once dailys.c. late afternoon, at the end of the light phase (LD 12:12) witheither vehicle or exendin-4 derivatives at the abovementioned doses for3 weeks. Body weight was recorded daily.

Statistical analyses were performed with Everstat 6.0 by repeatedmeasures two-way ANOVA and Dunnett's post-hoc analyses (glucose profile)and 1-way-ANOVA, followed by Dunnett's post-hoc test (body weight, bodyfat). Differences versus vehicle-treated DIO control mice wereconsidered statistically significant at the p<0.05 level.

Acute and Subchronic Effects of Exendin-4 Derivatives after SubcutaneousTreatment on Blood Glucose and HbA1c in Female Leptin-Receptor DeficientDiabetic db/db Mice (Method 3)

Female BKS.Cg-m+/+Leprdb/J (db/db) and BKS.Cg-m+/+Leprdb/+(lean control)mice were obtained from Charles River Laboratories, Germany, at an ageof 9-10 weeks. The animals were housed in groups in a specificpathogen-free barrier facility on a 12-h light/dark cycle with freeaccess to water and rodent-standard chow. After 1 week ofacclimatization, blood samples were drawn from the tail withoutanaesthesia and blood glucose (method: d-glucose hexokinase, hemolysate,AU640 Beckman Coulter) and HbA1c level (method: hemolysate, Cobas6000c501, Roche Diagnostics, Germany) were determined.

HbA1c is a glycosylated form of haemoglobin whose level reflects theaverage level of glucose to which the erythrocyte has been exposedduring its lifetime. In mice, HbA1c is a relevant biomarker for theaverage blood glucose level during the preceding 4 weeks (erythrocytelife span in mouse ˜47 days).

Db/db mice were stratified to treatment groups (n=8), so that each grouphad similar baseline blood glucose and HbA1c levels.

1) Acute effect on blood glucose in fed db/db mice: initial bloodsamples were taken just before first administration (s.c.) of vehicle(phosphate buffer solution) or exendin-4 derivatives at doses of 3, 10,and 100 μg/kg (dissolved in phosphate buffer), respectively. The volumeof administration was 5 mL/kg. The animals had access to water and chowduring the experiment, food consumption was determined at all timepoints of blood sampling. Blood glucose levels were measured at t=0.5 h,t=1 h, t=2 h, t=4 h, t=6 h, t=8 h, and t=24 h. Blood sampling wasperformed by tail incision without anaesthesia. Comparable data can beobtained for both female and male mice.

2) Subchronic effect on blood glucose and HbA1c: all animals weretreated once daily s.c. in the afternoon, at the end of the light phase(12 h lights on) with either vehicle or exendin-4 derivatives at theabovementioned doses for 4 weeks. At the end of the study, blood samples(tail, no anaesthesia) were analyzed for glucose and HbA1c. Comparabledata can be obtained for both female and male mice.

Statistical analyses were performed with Everstat 6.0 by repeatedmeasures two-way ANOVA and Dunnett's post-hoc analyses. Differencesversus vehicle-treated db/db control mice were considered statisticallysignificant at the p<0.05 level.

Effects of 4 Weeks of Treatment on Glucose, HbA1c and Oral GlucoseTolerance in Female Diabetic Dbdb-Mice (Method 4)

8 week old, female diabetic dbdb-mice of mean non-fasted glucose valueof 14.5 mmol/l and a body weight of 37-40 g were used. Mice wereindividually marked and were adapted to housing conditions for at leastone week.

7 days prior to study start, baseline values for non-fasted glucose andHbA1c were determined, 5 days prior to study start, mice were assignedto groups and cages (5 mice per cage, 10 per group) according to theirHbA1c values to ensure even distribution of lower and higher valuesbetween groups (stratification).

Mice were treated for 4 weeks, by once daily subcutaneous administration3 hours prior to the dark phase (6 pm to 6 am). Blood samples from atail tip incision were obtained for HbA1c on study day 21 and oralglucose tolerance was assessed in the 4th week. Oral glucose tolerancetest was done in the morning without prior extra compound administrationto majorly assess the effect of chronic treatment and less of acutecompound administration. Mice were fasted for 4 hours prior to oralglucose administration (2 g/kg, t=0 min). Blood samples were drawn priorto glucose administration and at 15, 30, 60, 90, 120, and 180 minthereafter. Feed was returned after the last blood sampling. Results arerepresented as change from baseline, glucose in mmol/l and HbA1c in %.

Statistical analyses are performed with Everstat Version 6.0 based onSAS by 1-way-ANOVA, followed by Dunnett's post-hoc test againstvehicle-control. Differences are considered statistically significant atthe p<0.05 level.

Glucose Lowering in Non-Fasted Female Diabetic dbdb-Mice

Female diabetic dbdb-mice of mean non-fasted glucose value of 20-22mmol/l and a body weight of 42 g+/−0.6 g (SEM) were used. Mice wereindividually marked and were adapted to housing conditions for at leastone week.

3-5 days prior to study start mice were assigned to groups and cages (4mice per cage, 8 per group) according to their non-fasted glucose valuesto ensure even distribution of lower and higher values between groups(stratification). On the study day, mice were weighed and dosed (t=0).Immediately prior to compound administration feed was removed whilewater remained available, and a first blood sample at a tail incisionwas drawn (baseline). Further blood samples were drawn at the tailincision at 30, 60, 90, 120, 240, 360, and 480 min.

Statistical analyses are performed with Everstat Version 6.0 based onSAS by 2-way-ANOVA on repeated measures, followed by Dunnett's post-hoctest against vehicle-control. Differences are considered statisticallysignificant at the p<0.05 level.

EXAMPLES

The invention is further illustrated by the following examples.

Example 1 Synthesis of SEQ ID NO: 20

The solid phase synthesis was carried out on Rink-resin with a loadingof 0.38 mmol/g, 75-150 μm from the company Agilent Technologies. TheFmoc-synthesis strategy was applied with HBTU/DIPEA-activation. Inposition 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH wasused in the solid phase synthesis protocol. The ivDde-group was cleavedfrom the peptide on resin according to literature (S. R. Chhabra et al.,Tetrahedron Lett. 39, (1998), 1603). Hereafter Fmoc-Glu-OtBu was coupledto the liberated amino-group employing the coupling reagents HBTU/DIPEAfollowed by Fmoc-deprotection with 20% piperidine in DMF. Finallyheneicosanyl chloride was coupled to the amino-group of Glu indichloromethane with DIPEA as base. The peptide was cleaved from theresin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int.J. Peptide Protein Res. 36, 1990, 255-266). The crude product waspurified via preparative HPLC on a Waters column (XBridge, BEH130, PrepC18 5 μM) using an acetonitrile/water gradient (both buffers with 0.05%TFA). The purified peptide was analysed by LCMS (Method C).Deconvolution of the mass signals found under the peak with retentiontime 31.67 min revealed the peptide mass 4647.40 which is in line withthe expected value of 4647.35.

Example 2 Synthesis of SEQ ID NO: 16

The solid phase synthesis was carried out on Novabiochem Rink-Amideresin(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamidonorleucylaminomethylresin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesisstrategy was applied with HBTU/DIPEA-activation. In position 1Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in thesolid phase synthesis protocol. The ivDde-group was cleaved from thepeptide on resin according to a modified literature procedure (S. R.Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazinehydrate in DMF. Hereafter Fmoc-Glu-OtBu was coupled to the liberatedamino-group employing the coupling reagents HBTU/DIPEA followed byFmoc-deprotection with 20% piperidine in DMF. Again Fmoc-Glu-OtBu wascoupled followed by Fmoc-deprotection and the final coupling of stearicacid using HBTU/DIPEA. The peptide was cleaved from the resin withKing's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. PeptideProtein Res. 36, 1990, 255-266). The crude product was purified viapreparative HPLC on a Waters column (Sunfire, Prep C18) using anacetonitrile/water gradient (both buffers with 0.05% TFA). The purifiedpeptide was analysed by LCMS (Method C). Deconvolution of the masssignals found under the peak with retention time 28.45 min revealed thepeptide mass 4733.6 which is in line with the expected value of 4734.4.

Example 3 Synthesis of SEQ ID NO: 17

The solid phase synthesis was carried out on Rink-resin with a loadingof 0.38 mmol/g, 75-150 μm from the company Agilent Technologies. TheFmoc-synthesis strategy was applied with HBTU/DIPEA-activation. Inposition 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH wasused in the solid phase synthesis protocol. The ivDde-group was cleavedfrom the peptide on resin according to literature (S. R. Chhabra et al.,Tetrahedron Lett. 39, (1998), 1603). Hereafter Fmoc-γ-amino butyric acidwas coupled to the liberated amino-group employing the coupling reagentsHBTU/DIPEA followed by Fmoc-deprotection with 20% piperidine in DMF.Finally stearic acid was coupled using HBTU/DIPEA. The peptide wascleaved from the resin with King's cocktail (D. S. King, C. G. Fields,G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crudeproduct was purified via preparative HPLC on a Waters column (XBridge,BEH130, Prep C18 5 μM) using an acetonitrile/water gradient (bothbuffers with 0.05% TFA). The purified peptide was analysed by LCMS(Method C). Deconvolution of the mass signals found under the peak withretention time 29.59 min revealed the peptide mass 4561.4 which is inline with the expected value of 4561.26.

Example 4 Synthesis of SEQ ID NO: 18

The solid phase synthesis was carried out on Rink-resin with a loadingof 0.38 mmol/g, 75-150 μm from the company Agilent Technologies. TheFmoc-synthesis strategy was applied with HBTU/DIPEA-activation. Inposition 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH wasused in the solid phase synthesis protocol. The ivDde-group was cleavedfrom the peptide on resin according to literature (S. R. Chhabra et al.,Tetrahedron Lett. 39, (1998), 1603). Hereafter Fmoc-β-Ala-OH was coupledto the liberated amino-group employing the coupling reagents HBTU/DIPEAfollowed by Fmoc-deprotection with 20% piperidine in DMF. AgainFmoc-β-Ala-OH was coupled followed by Fmoc-deprotection and the finalcoupling of stearic acid using HBTU/DIPEA. The peptide was cleaved fromthe resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields,Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product waspurified via preparative HPLC on a Waters column (XBridge, BEH130, PrepC18 5 μM) using an acetonitrile/water gradient (both buffers with 0.05%TFA). The purified peptide was analysed by LCMS (Method C).Deconvolution of the mass signals found under the peak with retentiontime 28.97 min revealed the peptide mass 4618.6 which is in line withthe expected value of 4618.32.

Example 5 Synthesis of SEQ ID NO: 9

The solid phase synthesis was carried out on Novabiochem Rink-Amideresin(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethylresin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesisstrategy was applied with HBTU/DIPEA-activation. In position 1Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in thesolid phase synthesis protocol. The ivDde-group was cleaved from thepeptide on resin according to a modified literature procedure (S. R.Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazinehydrate in DMF. Hereafter Palm-Glu(γOSu)-OtBu was coupled to theliberated amino-group. The peptide was cleaved from the resin withKing's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. PeptideProtein Res. 36, 1990, 255-266). The crude product was purified viapreparative HPLC on a Waters column (Sunfire, Prep C18) using anacetonitrile/water gradient (both buffers with 0.1% TFA). The purifiedpeptide was analysed by LCMS (Method B). Deconvolution of the masssignals found under the peak with retention time 12.7 min revealed thepeptide mass 4577.3 which is in line with the expected value of 4577.22.

Example 6 Synthesis of SEQ ID NO: 36

The solid phase synthesis was carried out on Novabiochem Rink-Amideresin(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethylresin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesisstrategy was applied with HBTU/DIPEA-activation. In position 1Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in thesolid phase synthesis protocol. The ivDde-group was cleaved from thepeptide on resin according to a modified literature procedure (S. R.Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazinehydrate in DMF. Hereafter Palm-Glu(γOSu)-OtBu was coupled to theliberated amino-group. The peptide was cleaved from the resin withKing's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. PeptideProtein Res. 36, 1990, 255-266). The crude product was purified viapreparative HPLC on a Waters column (Sunfire, Prep C18) using anacetonitrile/water gradient (both buffers with 0.05% TFA). The purifiedpeptide was analysed by LCMS (Method B). Deconvolution of the masssignals found under the peak with retention time 12.53 min revealed thepeptide mass 4489.57 which is in line with the expected value of4490.13.

Example 7 Synthesis of SEQ ID NO: 39

The solid phase synthesis was carried out on Novabiochem Rink-Amideresin(4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethylresin), 100-200 mesh, loading of 0.34 mmol/g. The Fmoc-synthesisstrategy was applied with HBTU/DIPEA-activation. In position 1Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in thesolid phase synthesis protocol. The ivDde-group was cleaved from thepeptide on resin according to a modified literature procedure (S. R.Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazinehydrate in DMF. Hereafter Palm-Glu(γOSu)-OtBu was coupled to theliberated amino-group. The peptide was cleaved from the resin withKing's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. PeptideProtein Res. 36, 1990, 255-266). The crude product was purified viapreparative HPLC on a Waters column (Sunfire, Prep C18) using anacetonitrile/water gradient (both buffers with 0.05% TFA). The purifiedpeptide was analysed by LCMS (Method B). Deconvolution of the masssignals found under the peak with retention time 13.5 min revealed thepeptide mass 4491.3 which is in line with the expected value of 4492.1.

In an analogous way, the following peptides SEQ ID NO: 8-41 weresynthesized and characterized (Method A-E), see Table 5.

TABLE 5 list of synthesized peptides and comparison of calculated vs.found molecular weight. SEQ ID NO: calc. Mass found mass  8 4576.24575.6  9 4577.2 4577.3 10 4478.0 4477.5 11 4462.1 4462.5 12 4548.14547.7 13 4506.1 4505.3 14 4561.2 4560.9 15 4605.3 4605.7 16 4734.44733.6 17 4561.3 4561.4 18 4618.3 4618.6 19 4648.3 4647.6 20 4647.44647.4 21 4520.1 4518.9 22 4464.0 4463.4 23 4565.1 4564.5 24 4522.14521.4 25 4579.1 4578.7 26 4620.2 4619.6 27 4563.2 4562.4 28 4504.14504.5 29 4477.0 4477.2 30 4420.0 4419.2 31 4505.1 4505.1 32 4477.14476.5 33 4519.1 4518.0 34 4533.2 4532.1 35 4449.0 4448.4 36 4490.14489.6 37 4491.1 4491.0 38 4590.3 4590.2 39 4492.1 4491.3 *40  4094.54092.3 *41  4194.6 4194.0 *non-acylated comparison compound

Example 8 Chemical Stability and Solubility

Solubility and chemical stability of peptidic compounds were assessed asdescribed in Methods. The results are given in Table 6.

TABLE 6 Chemical stability and solubility Stability Stability SolubilitySolubility (pH 4.5) (pH 7.4) (pH 4.5) (pH 7.4) SEQ ID NO: [%] [%][μg/ml] [μg/ml] Method 8 98.0 98.0 >1000 971.7 D 9 92.5 97.7 >1000 >1000D 12 100.0 95.3 >1000 >1000 D 13 86.8 95.9 267.7 >1000 D 14 96.094.0 >1000 >1000 D 15 91.0 90.0 997.0 >1000 D 17 100.0 100.0 970.0 >1000E 31 94.0 96.0 >1000 >1000 D 35 100.0 98.0 424.5 >1000 D

Example 9 In Vitro Data on GLP-1, GIP and Glucagon Receptor

Potencies of peptidic compounds at the GLP-1, GIP and glucagon receptorswere determined by exposing cells expressing human glucagon receptor(hGLUC R), human GIP (hGIP R) and human GLP-1 receptor (hGLP-1 R) to thelisted compounds at increasing concentrations and measuring the formedcAMP as described in Methods.

The results for Exendin-4 derivatives with activity at the human GIP(hGIP R), human GLP-1 receptor (hGLP-1 R) and human glucagon receptor(hGLUC R) are shown in Table 7.

TABLE 7 EC₅₀ values of exendin-4 peptide analogues at GLP- 1, GIP andGlucagon receptors (indicated in pM) EC50 hGIP R EC50 hGLP-1 R EC50hGLUC R SEQ ID NO: [pM] [pM] [pM] 8 9.8 5.3 18.3 9 5.7 3.6 7710.0 1015.1 13.2 40000.0 11 3.2 11.5 7220.0 12 8.9 12.7 1890.0 13 71.0 7.3 31.314 4.4 4.3 3760.0 15 8.2 8.1 5810.0 16 5.1 4.0 2890.0 17 9.6 8.7 9740.018 8.1 7.6 4950.0 19 13.8 4.0 707.5 20 24.5 23.2 3310.0 21 6.4 4.810100.0 22 16.6 32.0 11600.0 23 79.5 11.8 19100.0 24 23.5 13.5 38900.025 73.6 9.5 20500.0 26 19.7 4.9 8510.0 27 6.7 4.0 6390.0 28 10.9 3.2 9.929 127.0 7.0 46.8 30 22.1 12.0 226.0 31 6.5 6.0 3080.0 32 7.1 8.4 82.633 9.1 6.4 12900.0 34 22.2 4.6 11600.0 35 7.3 6.9 39100.0 36 6.4 3.45785.0 37 21.2 8.9 32.0 38 11.2 6.7 11.4 39 8.5 4.3 19300.0Comparison Testing

A selection of inventive exendin-4 derivatives comprising afunctionalized amino acid in position 14 has been tested versuscorresponding compounds having in this position 14 a‘non-functionalized’ amino acid. The reference pair compounds and thecorresponding EC50 values at GLP-1 and GIP receptors (indicated in pM)are given in Table 8. As shown, the inventive exendin-4 derivatives showa superior activity in comparison to the compounds with a‘non-functionalized’ amino acid in position 14.

TABLE 8 Comparison of exendin-4 derivatives comprising anon-functionalized amino acid in position 14 vs. exendin-4 derivativescomprising a functionalized amino acid in position 14. EC50 values atGLP-1 and GIP receptors are indicated in pM. (K = lysine, Nle =norleucine, L = leucine, γE-x53 = (S)-4-Carboxy-4-hexadecanoylamino-butyryl-) EC50 hGIP R EC50 hGLP-1 R residue in SEQ IDNO: [pM] [pM] position 14 32 7.1 8.4 K(γE-x53) 40 858 3.2 L 9 5.7 3.6K(γE-x53) 41 449 11.2 Nle

Example 10 Pharmacokinetic Testing

Pharmacokinetic profiles were determined as described in Methods.Calculated T_(1/2) and c_(max) values are shown in Table 9.

TABLE 9 Pharmacokinetic profiles of exendin-4 derivatives. Mice (1mg/kg) Mini pigs (0.1 mg/kg) SEQ ID NO: T_(1/2) [h] Cmax [ng/ml] T_(1/2)[h] Cmax [ng/ml] 8 3.4 3740 9 4.1 5470 12.2 278 10 2.7 5820 12 2.8 379013 3.1 3790 14 2.8 5340 15 3.5 5000 16 5.3 3460 18 2.1 5750 21 4.0 505019.1 479 26 3.7 3120 32 2.7 5520 34 2.8 5130

Example 11 Effect Of SEQ ID NO: 9 and SEQ ID NO: 13 on Gastric Emptyingand Intestinal Passage in Female NMRI-Mice

Female NMRI-mice, weighing on average 25-30 g, received 1, 3 and 10μg/kg of SEQ ID NO: 9, or 10 μg/kg of SEQ ID NO: 13 or phosphatebuffered saline (vehicle control) subcutaneously, 60 min prior to theadministration of the coloured bolus. 30 min later, the assessment ofstomach contents and intestinal passage was done (FIGS. 1 and 2).

In these studies, SEQ ID NO: 9 reduced intestinal passage by 49, 62 and64% (p<0.0001) and increased remaining gastric contents by 32, 79 and111% (p<0.0001), respectively. SEQ ID NO: 13 reduced intestinal passageby 60% (p<0.0001) and increased remaining gastric contents by 40%(p<0.0001), respectively. (p<0.0001 versus vehicle control, 1-W-ANOVA,followed by Dunnett's post-hoc test).

Example 12 Effect of SEQ ID NO: 12, SEQ ID NO: 13 and Liraglutide on22-Hours Food Intake in Female NMRI-Mice

Fed female NMRI-mice, weighing on average 25-30 g, were administered 0.1mg/kg of SEQ ID NO: 12, SEQ ID NO: 13, liraglutide or phosphate bufferedsaline (vehicle control) subcutaneously, directly prior to start offeeding monitoring. Lights-off phase (dark phase) started 4 hours later.All tested compounds induced a pronounced reduction of feed intake,reaching after 22 hours for liraglutide 47% (p=0.006), for SEQ ID NO: 1271% (p<0.0001) and SEQ ID NO: 13 93% (p=0.0003, 2-W-ANOVA-RM on ranks,post hoc Dunnett's Test) at the end of the study, respectively (FIG. 3a).

Effect of SEQ ID NO: 9 on 22-hours food intake in female NMRI-mice Fedfemale NMRI-mice, weighing on average 25-30 g, were administered 3 μg/kgor 10 μg/kg of SEQ ID NO: 9 or phosphate buffered saline (vehiclecontrol) subcutaneously, directly prior to start of feeding monitoring.Lights-off phase (dark phase) started 4 hours later.

SEQ ID NO: 9 induced a pronounced reduction of feed intake, reachingafter 22 hours for 3 μg/kg 11% (not significant, p=0.78), and for 10μg/kg 62% (p=0.0005, 2-W-ANOVA-RM on ranks, post hoc Dunnett's Test) atthe end of the study, respectively (FIG. 3b ).

Example 13 Subchronic Effects of SEQ ID NO: 9 after SubcutaneousTreatment on Blood Glucose and Body Weight in Female Diet-Induced Obese(DIO) C57BL/6NCrl Mice (18 Weeks on High-Fat Diet, Method 1)

1) Glucose Profile

Diet-induced obese female C57BL/6NCrl mice were administered daily inthe afternoon, at the end of the light phase (12 h lights on) with 10,30 and 100 μg/kg of SEQ ID NO: 9 or phosphate buffered solution (vehiclecontrol on standard or high-fat diet) subcutaneously. On day 6 oftreatment and at predefined time points, more blood samples were takento measure blood glucose and generate the blood glucose profile over 24h.

Already at the beginning of blood sampling on day 6 of treatment thebasal blood glucose levels were dose-dependently decreased compared toDIO control mice (FIG. 4).

2) Body Weight

Female obese C57BL/6NCrl mice were treated for 4 weeks once dailysubcutaneously in the afternoon, at the end of the light phase (12 hlights on) with 10, 30 or 100 μg/kg SEQ ID NO: 9 or vehicle. Body weightwas recorded daily, and body fat content was determined before the startof treatment and after 4 weeks of treatment.

Comparable data can be obtained for both female and male mice.

Treatment with SEQ ID NO: 9 reduced body weight, whereas in the high-fatdiet control group maintained body weight (FIG. 5 and Table 10).Calculating the relative body weight change from baseline valuesrevealed a dose-dependent decrease of body weight, varying between13.3-16.4% at 10 μg/kg, 17.6-20.9% at 30 μg/kg and 21.7-22.7% at 100μg/kg (FIG. 6). These changes resulted from a decrease in body fat, asshown by the absolute changes in body fat content (FIG. 7 and Table 10).

TABLE 10 Weight change in DIO mice over a 4- week treatment period (mean± SEM) Overall weight Bodyfat Example (Dose) change (g) change (g)Control standard diet −0.7 ± 0.2  1.5 ± 0.2 Control high-fat diet −0.98± 0.4  −0.8 ± 0.4 SEQ ID NO: 9 (10 μg/kg) −5.0 ± 0.5 −4.2 ± 0.4 SEQ IDNO: 9 (30 μg/kg) −6.9 ± 0.5 −6.1 ± 0.4 SEQ ID NO: 9 (100 μg/kg) −7.3 ±0.6 −6.4 ± 0.5 Liraglutide (100 μg/kg)  −3.9 ± −0.4 −3.3 ± 0.4

Example 14 Acute and Subchronic Effects of SEQ ID NO: 13, SEQ ID NO: 12,SEQ ID NO: 10 And SEQ ID NO: 9 after Subcutaneous Treatment on BloodGlucose and HbA1c in Female Leptin-Receptor Deficient Diabetic Db/DbMice (Method 3)

1) Glucose Profile

After blood sampling to determine the blood glucose baseline level, feddiabetic female db/db mice were administered 100 μg/kg of SEQ ID NO: 13,SEQ ID NO: 12, SEQ ID NO: 10 and SEQ ID NO: 9 or phosphate bufferedsolution (vehicle-treated db/db control) subcutaneously in the morning,at the beginning of the light phase (12 h lights on). At predefined timepoints, more blood samples were taken to measure blood glucose andgenerate the blood glucose profile over 24 h.

Comparable data can be obtained for both female and male mice.

At the tested dose, of SEQ ID NO: 13, SEQ ID NO: 12, SEQ ID NO: 10 andSEQ ID NO: 9 demonstrated a significant decrease in blood glucosecompared to db/db control mice, lasting longer than 24 h in the SEQ IDNO: 10 and SEQ ID NO: 9 dose group (FIG. 8).

2) Blood Glucose & HbA1c

Female diabetic mice were treated for 4 weeks once daily subcutaneouslywith 10, 30 or 100 μg/kg SEQ ID NO: 9 or vehicle in the morning, at thebeginning of the light phase (12 h lights on). Blood glucose and HbA1cwere determined before start of treatment and at the end of the studyafter 4 weeks of treatment. A strong and dose-dependent decrease inblood glucose, superior to liraglutide in the medium and highest dosecould be observed (FIG. 9). Before treatment started, no significantdifferences in blood glucose levels could be detected between db/dbgroups, only the lean control animals had significant lower glucoselevels. During the 4 weeks of treatment, glucose levels increased in thevehicle-treated db/db control group, indicating a worsening of thediabetic situation. All SEQ ID NO: 9—treated animals displayed asignificant lower blood glucose level than the db control mice at theend of the study.

Comparable data can be obtained for both female and male mice.

Corresponding to blood glucose, at start of the study, no significantdifferences in HbA1c levels could be detected between db/db groups, onlythe lean control animals had significant lower levels. During the 4weeks of treatment, HbA1c increased in the vehicle-treated db/db controlgroup, corresponding to the increasing blood glucose levels. Animalstreated with SEQ ID NO: 9 displayed a lower HbA1c level than the db/dbcontrol mice at the end of the study in all three doses (FIG. 10).

Example 15 Subchronic Effects of SEQ ID NO: 9 and SEQ ID NO: 21 afterSubcutaneous Treatment on Body Weight in Female Diet-Induced Obese (DIO)C57BL/6NCrl Mice (14 Weeks of Prefeeding with High-Fat Diet, Method 2)

Female obese C57BL/6NCrl mice were treated for 3 weeks once dailysubcutaneously in the late afternoon, prior the end of the light phase(12 h lights on) with 10 μg/kg SEQ ID NO: 9 and SEQ ID NO: 21 orvehicle. Body weight was recorded daily.

Treatment with SEQ ID NO: 9 and SEQ ID NO: 21 reduced body weight,whereas the high-fat diet control group even gained body weight (FIG. 11and Table 11). Calculating the relative body weight change from baselinevalues revealed a decrease of body weight up to 15.1% at 10 μg/kg SEQ IDNO: 9 and 18.0% at 10 μg/kg SEQ ID NO: 21 (FIG. 12).

TABLE 11 Weight change in DIO mice over a 3- week treatment period (mean± SEM) Example (Dose) Overall weight change (g) Control standard diet+0.3 ± 0.2 Control high-fat diet +2.7 ± 0.3 SEQ ID NO: 9 (10 μg/kg) −6.2± 0.4 SEQ ID NO: 21 (10 μg/kg) −7.3 ± 0.7

Example 16 Effects of 4 Weeks of Treatment with SEQ ID NO: 16, and SEQID NO: 21 on Glucose, HbA1c and Oral Glucose Tolerance in FemaleDiabetic dbdb-Mice (Method 4)

Female dbdb-mice, received 3 and 10 μg/kg of SEQ ID NO: 16 and 10 μg/kgof SEQ ID NO: 21 or phosphate buffered saline (vehicle control) oncedaily, subcutaneously over four weeks.

Both compounds reached a statistical significant reduction of non-fastedglucose compared to vehicle control at the 10 μg/kg dose (FIG. 13);p<0.05, 1-way-ANOVA, followed by Dunnett's post-hoc test.

Furthermore, both compounds prevented an increase of HbA1c in astatistical significant manner compared to vehicle control at the 10μg/kg dose (FIG. 14); (p<0.05, 1-way-ANOVA, followed by Dunnett'spost-hoc test). Treatment with SEQ ID NO: 16, and SEQ ID NO: 21 lead toimproved oral glucose tolerance (FIG. 15; represented as normalized to 0mmol/l at 0 min), and reduction of AUC under the glucose curve reachedstatistical significance compared to vehicle control (FIG. 16); (p<0.05,1-way-ANOVA, followed by Dunnett's post-hoc test).

Example 17 SEQ ID NO: 14 and SEQ ID NO: 21 on Glucose Lowering inNon-Fasted Female Diabetic Dbdb-Mice

Female dbdb-mice, received 3 μg/kg of SEQ ID NO: 14, SEQ ID NO: 21 orphosphate buffered saline (vehicle control) subcutaneously, at time 0min. Both compounds immediately lowered glucose values (baseline at20-22 mmol/l), with SEQ ID NO: 14 reaching the maximal effect of −8mmol/l (FIG. 18) and SEQ ID NO: 21 of 10-12 mmol/l glucose reduction(FIG. 17), respectively, at 240 min and keeping it to the end ofobservation at 480 min.

Both compounds reached a statistical significant reduction of glucosecompared to vehicle control from t=60 min until end of observation(p<0.05, 2-way-ANOVA on repeated measures, followed by Dunnett'spost-hoc test).

TABLE 12 Sequences SEQ ID NO: sequence 1H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2 2H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L- V-K-G-R-NH2 3H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K(γE-x53)-E-F-I- A-W-L-V-R-G-R-G 4Y-A-E-G-T-F-I-S-D-Y-S-I-A-M-D-K-I-H-Q-Q-D-F-V-N-W-L-L-A-Q-K-G-K-K-N-D-W-K-H-N-I-T-Q 5H-S-Q-G-T-F-T-S-D-Y-S-K-Y-L-D-S-R-R-A-Q-D-F-V-Q-W-L- M-N-T 6Y-G-E-G-T-F-T-S-D-L-S-I-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2 7Y-A-E-G-T-F-T-S-D-V-S-I-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V- K-G-R-NH2 8Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 9Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 10Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 11Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-K-R-A-A-Ai b-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 12Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-K-R-A-A-Q-D-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2 13Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-S-R-A-A-Q-D-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2 14Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x70)-E-K-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 15Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 16Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-γE-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 17Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(GABA-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 18Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(βA-βA-x70)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 19Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x70)-E-K-R-A-A-Q-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 20Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x76)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 21Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x70)-E-S-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 22Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 23Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Q-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 24Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Aib-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 25Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Q-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 26Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Q-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 27Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Aib-D-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 28Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-K-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 29Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-S-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 30Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-S-R-A-A-Aib-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 31Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-K-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 32Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 33Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 34Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 35Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Aib-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 36Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-K-R-A-A-Aib-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 37Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 38Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-D-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2 39Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-K(γE-x53)-E-S-R-A-A-Q-E-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 40Y-Aib-Q-G-T-F-T-S-D-L-S-I-Q-L-E-S-R-A-A-Q-D-F-I-E-W-L-K-A-G-G-P-S-S-G-A-P-P-P-S-NH2 41Y-Aib-E-G-T-F-T-S-D-L-S-I-Q-Nle-E-K-R-A-A-Aib-E-F-I-E-W-L-K-N-T-G-P-S-S-G-A-P-P-P-S-NH2

The invention claimed is:
 1. A peptidic compound having the formula (I):R¹—Z—R²  (I), or a salt or solvate thereof, wherein Z is a peptidemoiety having the formula (II): (II)Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-X40,

wherein: X3 is Glu, X12 is Ile, X14 is an amino acid residue having aside chain with a functionalized —NH₂ group, wherein the functionalized—NH₂ side chain group is functionalized by —C(O)—R⁵, wherein R⁵ is amoiety comprising up to 100 carbon atoms and optionally heteroatomsindependently selected from halogen, N, O, S and P, X15 is an amino acidresidue selected from Asp and Glu, X16 is an amino acid residue selectedfrom Ser, Lys, Glu, and Gln, X17 is an amino acid residue selected fromArg, Lys, Glu, Gln, Leu, Aib, Tyr, and Ala, X18 is an amino acid residueselected from Ala and Arg, X19 is an amino acid residue selected fromAla and Val, X20 is an amino acid residue selected from Gln, Aib, Lys,and His, X21 is an amino acid residue selected from Asp, Glu, and Leu,X28 is an amino acid residue selected from Asn and Ala, X29 is an aminoacid residue selected from Gly, Thr, and D-Ala, X40 is either absent oris Lys, R¹ is —NH₂, and R² is the C-terminal group of the peptidiccompound and is selected from —OH and —NH₂.
 2. The compound, salt, orsolvate of claim 1, wherein X14 is an amino acid residue with afunctionalized —NH₂ side chain group selected from functionalized Lys,Orn, Dab and Dap, wherein at least one H atom of the —NH₂ side chaingroup is replaced by —C(O)—R⁵, which is selected from the groupconsisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-Hexadecanoylamino-butyryl-,4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-,4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-,6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-,Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-,(S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl,(S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-,(S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-,(S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl-,(S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl-,(S)-4-Carboxy-4-tetradecanoylamino-butyryl-,(S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl-,(S)-4-Carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-,(S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-,(S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-,(S)-4-Carboxy-4-henicosanoylamino-butyryl-,(S)-4-Carboxy-4-docosanoylamino-butyryl-,(S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-,(S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-,(S)-4-Carboxy-4-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-,(S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-,(S)-4-Carboxy-4-icosanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,3-(3-Octadecanoylamino-propionylamino)-propionyl-,3-(3-Hexadecanoylamino-propionylamino)-propionyl-,3-Hexadecanoylamino-propionyl-,(S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-,(S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-,(S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-,tetradecanoyl-, 11-Carboxy-undecanoyl-,11-Benzyloxycarbonyl-undecanoyl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylamino)-butyryl-,6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-,6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-,4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-,4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,(S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl-,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-,2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl-,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1H-tetrazol-5-yl-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-,2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(11-carboxy-undecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-,and(S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-.3. The compound, salt, or solvate of claim 1, wherein X14 is Lys,wherein the —NH₂ side chain group is functionalized by one of the groupsselected from the group consisting of(S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-octadecanoylamino-butyryl-, Hexadecanoyl-,(S)-4-Carboxy-4-henicosanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,and 3-(3-Octadecanoylamino-propionylamino)-propionyl-.
 4. The compound,salt, or solvate of claim 1, wherein X14 is Lys functionalized by one ofthe groups selected from the group consisting of(S)-4-carboxy-4-hexadecanoylamino-butyryl (γE-x53),(S)-4-carboxy-4-octadecanoylamino-butyryl (γE-x70),(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl(γE-γE-x70), 4-octadecanoylamino-butyryl (GABA-x70),(S)-4-Carboxy-4-henicosanoylamino-butyryl (γE-x76), and3-(3-Octadecanoylamino-propionylamino)-propionyl (β-Ala-β-Ala-x70). 5.The compound, salt, or solvate of claim 1, wherein R² is —NH₂.
 6. Thecompound, salt, or solvate of claim 1, wherein: X3 is Glu, X12 is Ile,X14 is Lys, wherein the —NH₂ side chain group is functionalized by oneof the groups selected from the group consisting of(S)-4-Carboxy-4-hexadecanoylamino-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,3-(3-Octadecanoylamino-propionylamino)-propionyl-4-octadecanoylamino-butyryl-,and (S)-4-Carboxy-4-henicosanoylamino-butyryl-, X15 is an amino acidresidue selected from Glu and Asp, X16 is an amino acid residue selectedfrom Ser and Lys, X17 is Arg, X18 is Ala, X19 is Ala, X20 is an aminoacid residue selected from Gln and Aib, X21 is an amino acid residueselected from Asp and Glu, X28 is an amino acid residue selected fromAsn and Ala, X29 is an amino acid residue selected from Gly and Thr, andX40 is absent.
 7. The compound, salt, or solvate of claim 1, wherein X14is Lys, wherein the —NH₂ side chain group is functionalized by one ofthe groups selected from the group consisting of(S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-octadecanoylamino-butyryl-,(S)-4-Carboxy-4-henicosanoylamino-butyryl-,(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-,and 3-(3-Octadecanoylamino-propionylamino)-propionyl-.
 8. The compound,salt, or solvate of claim 1, wherein X14 is Lys, wherein the —NH₂ sidechain group is functionalized by one of the groups selected from thegroup consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, and(S)-4-Carboxy-4-octadecanoylamino-butyryl-.
 9. The compound, salt, orsolvate of claim 1, wherein: X3 is Glu, X12 is Ile, X14 is Lys, whereinthe —NH₂ side chain group is functionalized by one of the groupsselected from the group consisting of(S)-4-Carboxy-4-hexadecanoylamino-butyryl- and(S)-4-Carboxy-4-octadecanoylamino-butyryl-, X15 is an amino acid residueselected from Glu and Asp, X16 is an amino acid residue selected fromSer and Lys, X17 is Arg, X18 is Ala, X19 is Ala, X20 is an amino acidresidue selected from Gln and Aib, X21 is an amino acid residue selectedfrom Asp and Glu, X28 is an amino acid residue selected from Asn andAla, X29 is an amino acid residue selected from Gly and Thr, and X40 isabsent.
 10. The compound, salt, or solvate of claim 1, wherein X19 isAla.
 11. The compound, salt, or solvate of claim 1, wherein X28 is Ala,and X29 is Gly.
 12. The compound, salt, or solvate of claim 1, whereinX28 is Asn, and X29 is Thr.
 13. The compound, salt, or solvate of claim1, wherein: X3 is Glu, X12 is Ile, X14 is Lys, wherein the —NH₂ sidechain group is functionalized by one of the groups selected from thegroup consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-x53),(S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-x70),(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-(γE-γE-x70),3-(3-Octadecanoylamino-propionylamino)-propionyl-(βA-βA-x70),4-octadecanoylamino-butyryl-(GABA-x70), and(S)-4-Carboxy-4-henicosanoylamino-butyryl-(γE-x76), X15 is an amino acidresidue selected from Asp and Glu, X16 is an amino acid residue selectedfrom Ser and Lys, X17 is Arg, X18 is Ala, X19 is Ala, X20 is an aminoacid residue selected from Gln and Aib, X21 is an amino acid residueselected from Asp and Glu, X28 is an amino acid residue selected fromAsn and Ala, X29 is an amino acid residue selected from Gly and Thr, andX40 is absent.
 14. The compound, salt, or solvate of claim 1, wherein:X3 is Glu, X12 is Ile, X14 is Lys, wherein the —NH₂ side chain group isfunctionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-x53),X15 is an amino acid residue selected from Asp and Glu, X16 is an aminoacid residue selected from Ser and Lys, X17 is Arg, X18 is Ala, X19 isAla, X20 is an amino acid residue selected from Gln and Aib, X21 is anamino acid residue selected from Asp and Glu, X28 is an amino acidresidue selected from Asn and Ala, X29 is an amino acid residue selectedfrom Gly and Thr, and X40 is absent.
 15. The compound, salt, or solvateof claim 1, wherein: X3 is Glu, X12 is Ile, X14 is Lys, wherein the —NH₂side chain group is functionalized by one of the groups selected fromthe group consisting of(S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-x70),(S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-(γE-γE-x70),3-(3-Octadecanoylamino-propionylamino)-propionyl-(βA-βA-x70),4-octadecanoylamino-butyryl-(GABA-x70), and(S)-4-Carboxy-4-henicosanoylamino-butyryl-(γE-x76), X15 is Glu, X16 isan amino acid residue selected from Ser and Lys, X17 is Arg, X18 is Ala,X19 is Ala, X20 is an amino acid residue selected from Gln and Aib, X21is Glu, X28 is an amino acid residue selected from Asn and Ala, X29 isan amino acid residue selected from Gly and Thr, and X40 is absent. 16.The compound of claim 1, wherein the compound is selected from those ofSEQ ID NOs: 9-12, 14-27, 31, 33-36 and 39, or a salt or solvate thereof.17. The compound of claim 1, wherein the compound is selected from thoseof SEQ ID NOs: 9, 10, 12, 14-27, 31, and 33-36, or a salt orsolvate-thereof.
 18. The compound of claim 16, wherein the compound isselected from those of SEQ ID NOs: 9-12, and 39, or a salt or solvatethereof.
 19. The compound of claim 17, wherein the compound is selectedfrom those of SEQ ID NOs: 9, 10 and 12, or a salt or solvate thereof.20. The compound of claim 16, wherein the compound is selected fromthose of SEQ ID NOs: 14-21, or a salt or solvate thereof.
 21. Thecompound of claim 16, wherein the compound is selected from those of SEQID NOs: 22-27, 31, and 33-36, or a salt or solvate thereof.
 22. Apharmaceutical composition comprising a peptidic compound having theformula (I):R¹—Z—R²  (I), or a salt, or solvate thereof, wherein Z is a peptidemoiety having the formula (II): (II)Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-X40,

wherein: X3 is Glu, X12 is Ile, X14 is an amino acid residue having aside chain with a functionalized —NH₂ group, wherein the functionalized—NH₂ side chain group is functionalized by —C(O)—R⁵, wherein R⁵ is amoiety comprising up to 100 carbon atoms and optionally heteroatomsindependently selected from halogen, N, O, S and P, X15 is an amino acidresidue selected from Asp and Glu, X16 is an amino acid residue selectedfrom Ser, Lys, Glu and Gln, X17 is an amino acid residue selected fromArg, Lys, Glu, Gln, Leu, Aib, Tyr, and Ala, X18 is an amino acid residueselected from Ala and Arg, X19 is an amino acid residue selected fromAla and Val, X20 is an amino acid residue selected from Gln, Aib, Lys,and His, X21 is an amino acid residue selected from Asp, Glu, and Leu,X28 is an amino acid residue selected from Asn and Ala, X29 is an aminoacid residue selected from Gly, Thr, and D-Ala, X40 is either absent oris Lys, R¹ is —NH₂, and R² is the C-terminal group of the peptidiccompound and is selected from —OH, and —NH₂.
 23. The pharmaceuticalcomposition of claim 22, wherein the compound having the formula (I), ora salt or solvate thereof, is present as an active agent, and whereinthe pharmaceutical composition further comprises at least onepharmaceutically acceptable carrier.
 24. A solvate of a compound ofclaim
 1. 25. A hydrate of a compound of claim
 1. 26. The compound, salt,or solvate of claim 1, wherein R⁵ is a moiety comprising up to 50 carbonatoms and optionally heteroatoms selected from halogen, N, O, S and P.27. A peptidic compound with reduced relative activity, the compoundhaving the formula (I):R¹—Z—R²  (I), or a salt, or solvate thereof, wherein Z is a peptidemoiety having the formula (II): (II)Tyr-Aib-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-X12-Gln-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-X40,

wherein: X3 is Glu, X12 is Ile, X14 is an amino acid residue having aside chain with a functionalized —NH₂ group, wherein the functionalized—NH₂ side chain group is functionalized by —C(O)—R⁵, wherein R⁵ is amoiety comprising up to 100 carbon atoms and optionally heteroatomsindependently selected from halogen, N, O, S and P, X15 is an amino acidresidue selected from Asp and Glu, X16 is an amino acid residue selectedfrom Ser, Lys, Glu, and Gln, X17 is an amino acid residue selected fromArg, Lys, Glu, Gln, Leu, Aib, Tyr, and Ala, X18 is an amino acid residueselected from Ala and Arg, X19 is an amino acid residue selected fromAla and Val, X20 is an amino acid residue selected from Gln, Aib, Lys,and His, X21 is an amino acid residue selected from Asp, Glu, and Leu,X28 is an amino acid residue selected from Asn and Ala, X29 is an aminoacid residue selected from Gly, Thr, and D-Ala, X40 is either absent oris Lys, R¹ is —NH₂, and R² is the C-terminal group of the peptidiccompound and is selected from —OH, and —NH₂, and wherein the reducedrelative activity comprises a relative activity of at least 0.04% to atleast 0.5% compared to that of natural Glucose-dependent insulinotropicpolypeptide (GIP) at the GIP receptor, Glucagon-like peptide 1 (7-36)(GLP-1 (7-36)) at the GLP-1 receptor, or natural glucagon at theglucagon receptor.
 28. The compound, salt, or solvate of claim 27,wherein the compound has a relative activity of at least 0.04% comparedto that of natural GIP at the GIP receptor.
 29. The compound, salt, orsolvate of claim 28, wherein the compound has a relative activity of atleast 0.2% compared to that of natural GIP at the GIP receptor.
 30. Thecompound, salt, or solvate of claim 27, wherein the compound exhibits arelative activity of at least 0.07% compared to that of GLP-1(7-36) atthe GLP-1 receptor.
 31. The compound, salt, or solvate of claim 30,wherein the compound exhibits a relative activity of at least 0.4%compared to that of GLP-1(7-36) at the GLP-1 receptor.
 32. The compound,salt, or solvate of claim 27, wherein the compound further exhibits arelative activity of at least 0.1% compared to that of natural glucagonat the glucagon receptor.
 33. The compound, salt, or solvate of claim32, wherein the compound further exhibits a relative activity of atleast 0.5% compared to that of natural glucagon at the glucagonreceptor.
 34. A peptidic compound consisting of the amino acid sequenceof SEQ ID NO: 9 or a salt or solvate thereof.
 35. A peptidic compoundconsisting of the amino acid sequence of SEQ ID NO: 12 or a salt orsolvate thereof.
 36. A peptidic compound consisting of the amino acidsequence of SEQ ID NO: 14 or a salt or solvate thereof.
 37. A peptidiccompound consisting of the amino acid sequence of SEQ ID NO: 16 or asalt or solvate thereof.
 38. A peptidic compound consisting of the aminoacid sequence of SEQ ID NO: 17 or a salt or solvate thereof.
 39. Apeptidic compound consisting of the amino acid sequence of SEQ ID NO: 18or a salt or solvate thereof.
 40. A peptidic compound consisting of theamino acid sequence of SEQ ID NO: 20 or a salt or solvate thereof.
 41. Apeptidic compound consisting of the amino acid sequence of SEQ ID NO: 21or a salt or solvate thereof.
 42. A pharmaceutical compositioncomprising a peptidic compound consisting of the amino acid sequence ofSEQ ID NO: 9 or a salt or solvate thereof.
 43. A pharmaceuticalcomposition comprising a peptidic compound consisting of the amino acidsequence of SEQ ID NO: 12 or a salt or solvate thereof.
 44. Apharmaceutical composition comprising a peptidic compound consisting ofthe amino acid sequence of SEQ ID NO: 14 or a salt or solvate thereof.45. A pharmaceutical composition comprising a peptidic compoundconsisting of the amino acid sequence of SEQ ID NO: 16 or a salt orsolvate thereof.
 46. A pharmaceutical composition comprising a peptidiccompound consisting of the amino acid sequence of SEQ ID NO: 17 or asalt or solvate thereof.
 47. A pharmaceutical composition comprising apeptidic compound consisting of the amino acid sequence of SEQ ID NO: 18or a salt or solvate thereof.
 48. A pharmaceutical compositioncomprising a peptidic compound consisting of the amino acid sequence ofSEQ ID NO: 20 or a salt or solvate thereof.
 49. A pharmaceuticalcomposition comprising a peptidic compound consisting of the amino acidsequence of SEQ ID NO: 21 or a salt or solvate thereof.